Wellcome Witnesses to
Twentieth Century Medicine
Haemophilia: Recent History of
The transcript of a Witness Seminar held at
the Wellcome Institute for the History of Medicine,
London, on 10 February 1998
Volume Four- September 1999
Witness Seminar Transcript edited by:
E M Tansey D A Christie
©The Trustee of the Wellcome Trust, London, 1 999
First published by the Wellcome Trust, 1999
The Wellcome Trust is a registered charity, no. 210183.
ISBN 978 184129 008 9
All volumes are freely available online at: www.history.qmul.ac.uklresearch/modbiomed/wellcome_witnesses/
Please cite as: Tansey E M, Christie DA. (eds) (1999) Haemophilia: Recent history of clinical
management. Wellcome Witnesses to Twentieth Century Medicine, vol.4. London:
Front cover photographs, L to R from the top:
Dr James Matthews
Professor Stuart Douglas (1921-98), Sir Christopher Booth
Dr James Matthews, Dr Use Wilkinson, Mr Ross Dike
Professor Christine Lee (chair), Mr Clifford Welch
Professor Christine Lee (chair), Rev'd Alan Tanner
Professor llsley Ingram (1919-2004), Professor Robert Duthie (1925-2005)
Mr Clifford Welch, Dr Charles Rizza
Dr Peter Jones, Dr Ethel Bidwell (d. 2003)
Back cover photographs, L to R from the top
Dr Peter Jones, Rev'd Alan Tanner
Dr Gordon Cook, Dr David Tyrrell (1925-2005), Dr Use Wilkinson
Dr Helen Dodsworth, Dr David Evans
Dr Sheila Howarth (1920-2000)
Dr Peter Jones, Rev'd Alan Tanner
Dr David Evans
Rev'd Alan Tanner, Professor Christine Lee (chair)
e m tansey
Haemophilia: Recent History of Clinical Management
editors : D A Christie and E M Tansey
Haemophilia is a rare disorder of the clotting mechanisms of the blood. Estimates
of its prevalence in the United Kingdom range from 1 in 4000 to 1 in 10 000 of
the male population. But haemophilia has achieved a prominence out of all
proportion to its incidence. Several factors have contributed to the reputation of
the disease: the idea that blood, the very life-carrying force itself, can cause pain,
incapacity and eventually death, is in itself deeply shocking. So too is the vision of
small boys suffering the tragic consequences of the disease, added to which is its
'hidden' transmission through unaffected mothers, and in particular its passage
via descendants of Queen Victoria through European Royal families. The role of
the notorious Siberian monk Rasputin, whose ability to 'cure' the Tsarevitch
Alexey's bleeding led to his sinister involvement with the Russian Royal family,
may even have contributed to the Russian Revolution.
This Witness Seminar examined the changes that have occurred in the
treatment and clinical management of haemophilia in the past half-century, by
inviting scientists, haematologists, carers and haemophiliacs themselves to a
meeting at which advances and some of the disastrous reversals of the past 50
years were discussed. At the end of the second world war, treatment for
haemophilia had advanced little - immobilization of painfully swollen joints into
which uncontrolled bleeding took place was the main treatment. Suffering
children with a short life expectancy were condemned to lie in bed-ridden pain,
and several Witnesses here recall wards of small boys with limbs in plaster.
Therapies were limited. Some, like Russell's viper venom, offered limited relief, or
like Timperley's egg white, held out the hope of relief. For many, the most
reliable method of treatment was whole blood transfusion, and here one Witness,
Clifford Welch, himself a sufferer of a mild form of haemophilia, recalls the
extraordinary situation in which his triplet siblings, all haemophiliacs, frequently
received life saving transfusions from their mother (page 40). As Welch
emphasizes, the history of haemophilia during the past 50 years has seen 'an
extraordinary transformation' (page 76) .
That extraordinary transformation began in the 1930s, at a time when the
life expectancy of a haemophiliac was only 20 years. Experimental research and
laboratory investigations into clotting mechanisms lead to the 'cascade' hypothesis
See for example Orlando Figes (1996) A People's Tragedy: The Russian revolution, 1891—1924.
London: Pimlico, 24—34.
of blood coagulation (see Appendix, page 79) and the identification of a number
of different clotting factors. The development of blood transfusion services during
the second world war lead to improvements in fractionation techniques and the
production of therapeutic plasma for transfusion, although an ominous portent of
things to come was the recognition of post-transfusion jaundice, transmitted
through pooled plasma.
A major breakthrough was made in Oxford in the 1950s when Ethel Bidwell
first prepared factor VIII concentrate, although its bespoke production meant
that its availability was limited until the mid 1960s. In the present volume, Dr
Bidwell and her contemporaries discuss those early days, and the seemingly
primitive conditions in which blood was collected from local abattoirs,
transported across Oxford, and then fractionated in poorly equipped labs.
Photographs of this period (pages 48-51), generously provided by Mr Ross Dike,
Dr Bidwell's assistant, emphasize not only the makeshift nature of this life-saving
enterprise, but also the dedication and determination of those involved in this
Isolation of further factors and the involvement of commercial producers and
the National Blood Transfusion Service all provided increased treatment options
for haemophiliacs, and the wider availability of cryoprecipitate in the 1960s lead
to a further revolution - home treatment pioneered in particular by Kathleen
Dormandy at the Royal Free Hospital, often in the face of strong disapproval
from medical colleagues. Home treatment opened up another door to a normal
life for sufferers and their families. That door to normality was cruelly slammed
shut by the tragedy, many here use the word scandal, of contamination of blood
products, many imported because of economy measures, with hepatitis viruses,
HIV, and even now the spectre of CJD haunts haemophiliacs and their families.
Haemophilia and the rights of haemophiliacs moved from the purely medical
arena into the political spotlight as issues of compensation, or recompense (see
page 65), were successively debated and fought over by pressure groups. The
effect of litigation against doctors, many of whom had warned Government and
health authorities of the potential problems of relying on imported blood
products, adds a particularly poignant flavour to the story, as does the tragedy of
the devastation of the haemophilic community. One Witness speaks movingly of
three generations decimated by HIV infection and AIDS (page 66).
Haematologists and paediatricians had to become rapidly knowledgeable about
virology and safe sex, the latter an uncomfortable subject to raise in a children's
hospital (see page 27).
As well as the straight scientific and clinical advances, other important issues
emerge from this meeting, some more obvious then others. The setting up of the
United Kingdom Haemophilia Centre Directors Organization, so that those
treating this rare condition could benefit from shared experiences, emerged in a
haphazard way, spearheaded by Rosemary Biggs, who was unable to come to the
meeting, but who, in a pre-recorded interview told how she organized parties,
believing that as a woman she could hold a party and not offend anyone,
although if she called a formal academic meeting feathers might be ruffled. A less
obvious area for discussion was the impact of material technology, as plastic
containers, disposable needles and catheters, and ready-made butterfly needles
improved the preparation and administration of therapeutic products. Some here
tell harrowing tales of resharpened needles, many so old that they became
hooked, blocking in the middle of an injection into a deeply distressed child, and
of a traumatized boy having to be sedated daily to receive life-saving treatment.
These are just a selection of the issues that are covered here by our Witnesses,
to whom we are grateful for the time they gave us not only in planning
and holding this meeting, but also during the editorial process, as we have
sought to transform a spoken meeting into readable text, and to provide
To date, the Wellcome Trust's History of Twentieth Century Medicine
Group has held 21 Witness Seminars, most of which have been published, as
listed in the Table below. For the Haemophilia meeting we are especially grateful
to Professor Christine Lee for suggesting the subject, assisting us so
enthusiastically in organizing the meeting, and chairing it so efficiently; Ross
Dike kindly displayed a selection of his photographs at the meeting and has
allowed us to reproduce some of them here; and Dr Huw Dorkins kindly read the
edited transcript for general sense and understandability, and offered suggestions
for glossary terms. As with all our meetings, we hope that even if the precise
details of some of the technical sections are not clear to the non-specialist reader,
the sense and significance of the events are understandable. We are grateful to our
colleagues in the Wellcome Trust for their help in running these meetings, and
wish to mention in particular the assistance of the Audiovisual Department, the
Medical Photographic Library, and the Publishing Department, especially Julie
Wood who has supervised the design and production of the published volume.
Mrs Jaqui Carter is our transcriber, and Mrs Wendy Kutner and Mrs Lois
Reynolds assist us in running the meetings. Finally we thank the Wellcome Trust
for supporting this programme.
Wellcome Institute for the History of Medicine
Tansey, E M. (ed.) (1998) Witnessing medical history: an interview with Dr Rosemary Biggs,
conducted by Professor Christine Lee and Dr Charles Rizza. Haemophilia 4: 769-777 '.
History of Twentieth Century Medicine Witness Seminars, 1993-1999
1993 Monoclonal antibodies
Organizers: Dr E M Tansey and Dr Peter Catterall
1 994 The early history of renal transplantation
Organizer: Dr Stephen Lock
Pneumoconiosis of coal workers
Organizer: Dr E M Tansey
1995 Self and non-self: a history of autoimmunity
Organizers: Sir Christopher Booth and Dr E M Tansey
Ashes to ashes: the history of smoking and health
Organizers: Dr Stephen Lock and Dr E M Tansey
Organizers: Dr Lara Marks and Dr E M Tansey
Organizer: Dr E M Tansey
1996 Committee on Safety of Drugs
Organizers: Dr Stephen Lock and Dr E M Tansey
Making the body more transparent: the impact of
nuclear magnetic resonance and magnetic resonance imaging
Organizer: Sir Christopher Booth
3 Published in Tansey E M, Catterall P P, Christie D A, Willhoft S V, Reynolds L A. (1997) (eds)
Wellcome Witnesses To Twentieth Century Medicine, vol. 1. London: Wellcome Trust, 135pp.
P DArcy Hart, edited and annotated by E M Tansey. (1998) Chronic pulmonary disease in South
Wales coalmines: An eye-witness account of the MRC surveys (1937-1942). Social History of Medicine
Lock S P, Reynolds L A, Tansey E M. (eds) (1998,) Ashes to Ashes — The history of smoking and
health. London: Wellcome Trust, 198-220.
Published in Tansey E M, Christie D A, Reynolds L A. (eds) (1998) Wellcome Witnesses to
Twentieth Century Medicine, vol. 2. London: The Wellcome Lrust, 282 pp.
1997 Research in General Practice
Organizers: Dr Ian Tait and Dr E M Tansey
Drugs in psychiatric practice
Organizers: Dr E M Tansey and Dr David Healy
The MRC Common Cold Unit 6
Organizers: Dr David Tyrrell and Dr E M Tansey
The first heart transplant in the UK
Organizer: Professor Tom Treasure
1998 Haemophilia: recent history of clinical management
Organizers: Dr E M Tansey and Professor Christine Lee
Obstetric ultrasound: historical perspectives
Organizers: Dr Malcolm Nicolson, Mr John Fleming and Dr E M Tansey
Organizers: Dr Robert Bud and Dr E M Tansey
Clinical research in Britain, 1950-1980
Organizers: Dr David Gordon and Dr E M Tansey
1999 Intestinal absorption
Organizers: Sir Christopher Booth and Dr E M Tansey
The MRC Epidemiology Unit (South Wales)
Organizers: Dr Andy Ness and Dr E M Tansey
Neonatal intensive care
Organizers: Professor Osmund Reynolds, Dr David Gordon and Dr E M Tansey
British contribution to medicine in Africa after the second world war
Organizers: Dr Mary Dobson, Dr Maureen Malowany, Dr Gordon Cook and
Dr E M Tansey
Tansey E M, Reynolds L A. (eds) (1999) Early heart transplant surgery in the UK.
Wellcome Witnesses to Twentieth Century Medicine, vol. 3. London: The Wellcome Trust, 72 pp.
Tansey E M, Christie D A. (eds) (1999) Haemophilia: Recent history of clinical management.
Wellcome Witnesses to Twentieth Century Medicine, this volume.
Haemophilia: Recent History of Clinical
The transcript of a Witness Seminar held at the Wellcome Institute
for the History of Medicine, London, on 10 February 1998
Edited by D A Christie and E M Tansey
Haemophilia: Recent History
of Clinical Management
Dr Derek Bangham
Dr Ethel Bidwell
Sir Christopher Booth
Dr Brian Colvin
Dr Angela Dike
Mr Ross Dike
Dr Helen Dodsworth
Professor Stuart Douglas*
Professor Robert Duthie
Dr David Evans
Dr Sheila Howarth
Professor Ilsley Ingram
Dr Peter Jones
Professor Christine Lee (Chair)
Dr James Matthews
Mrs Riva Miller
Dr Charles Rizza
Rev Alan Tanner
Dr Tilli Tansey
Professor Edward Tuddenham
Dr David Tyrrell
Mr Clifford Welch
Others present at the meeting: Dr Trevor Barrowcliffe, Ms Jacqui
Dr J K Smith, Miss Rosemary Spooner
Apologies: Professor Jean-Pierre Allain, Dr Donald Bateman, Dr Rosemary
Biggs, Mrs Peggy Britten,** Professor Judith Chessells, Dr Audrey Dawson,
Mr Ron Hutton, Professor Ralph Kekwick, Professor Sir David Weatherall
*Deceased 15 November 1998
**Deceased 1 March 1999
Haemophilia: Recent history
Professor Christine Lee: 1 I think haemophilia is one of the best areas of
clinical medicine where we have seen a very rapid introduction of scientific
discovery into clinical practice. All of us who work on haemophilia realize that
this has gone on very much with cooperation between the patients and the
scientists and the doctors. I first saw haemophilia in 1967 when I was a medical
student in Oxford and we were doing our orthopaedics at the Nuffield
Orthopaedic Hospital. I have a very clear memory of a ward of little boys with
their legs strung up, their arms strung up, and I think there was a schoolroom
nearby. It was with great pleasure that last week we were able to talk with Dr
Rosemary Biggs, who with Macfarlane, put haemophilia care on the map in
Oxford from the late 1940s onwards. 3 Unfortunately, Dr Biggs wasn't able to
be with us today, but I am hoping that throughout the discussions this afternoon
I can interject some of her comments, and try and raise memories from you and
our invited speakers. What I am going to try very hard to do - I do have a kind
1 Professor Christine Lee FRCP FRCPath DSc(Med) (b. 1943) qualified from the University
of Oxford Medical School and has been Professor of Haemophilia and Director and
Consultant Haematologist at the Haemophilia Centre and Haemostasis Unit, The Royal Free
Hospital, London, since 1987 and is a member of the International Society of Thrombosis &
Haemostasis. She has published many papers on the side-effects of blood product therapy in
haemophilia, particularly hepatitis and acquired immune deficiency syndrome (AIDS).
2 Dr Rosemary Biggs MD FRCP (b. 1912) first joined Gwyn Macfarlane in Oxford in 1945
in his studies on fibrinolysis. She is co-author on many papers including the seminal paper on
Christmas disease (see for example notes 3, 17, 18, 23, 37 and 198). When the Medical Research
Council Blood Coagulation Unit in Oxford closed in 1967, Dr Biggs became Director of the
newly opened Haemophilia Centre. She was Secretary of the UKHCDO from 1968 to 1977.
See Tansey E M. (ed.) (1998) Witnessing medical history: an interview with Dr Rosemary
Biggs, conducted by Professor Christine Lee and Dr Charles Rizza. Haemophilia 4: 769-777.
3 Professor R G Macfarlane CBE FRCP FRCPS FRS (1907-1987) qualified in medicine
from St Bartholomew's Hospital in 1933 and in 1936 he became Clinical Assistant
Pathologist at the Postgraduate Medical School Hammersmith. He was appointed clinical
pathologist to the Radcliffe Infirmary, Oxford in 1940 and was Radcliffe lecturer in
haematology in 1943. He was joined by Dr Rosemary Biggs (see note 2 above) and Dr Ethel
Bidwell (see note 47 below) and together they collaborated closely on extensive studies of
fibrinolysis and purification and concentration of the various blood-clotting factors. He
became Director of the Blood Coagulation Research Unit in Oxford in 1959, Fellow of All
Souls College, Oxford, in 1963, Professor of Clinical Pathology in the University of Oxford
in 1965, and President of the Haemophilia Society in 1981. The Macfarlane Trust was
established in his memory to administer funds to haemophiliacs infected with HIV through
treatment with blood products. See Born G V R, Weatherall D J. (1990) Robert Gwyn
Macfarlane. Biographical Memoirs of Fellows of the Royal Society 35: 211-239. Robb-Smith A
(1993) Life and Achievements of Professor Robert Gwyn Macfarlane FRS Pioneer in the Care of
Haemophiliacs. London: Royal Society of Medicine Services Limited. See also Biggs R. (1967)
Thirty years of haemophilia treatment in Oxford. British Journal of Haematology 13: 452-463.
Haemophilia: Recent history
of programme here, but I am told by Dr Tansey that these things tend to go off
in ways which nobody can predict - is to try by the end of the afternoon to have
covered the introduction of treatment and the organization of haemophilia, and
to talk a bit about some of the disastrous side-effects and the impact that that
has had on us all. So without going on any more, I am going to start by asking
Ilsley Ingram, who was Professor of Experimental Haematology at St
Thomas' Hospital, and has an amazing history to tell us, and perhaps, Ilsley,
you could begin a bit at the beginning and talk about when you first got into
Professor Ilsley Ingram: 4 I have made a note of some landmarks in the
history of haemophilia. 5 The earliest known written reference to abnormal post-
traumatic bleeding in maternally-related males is from rabbinical references
from the second century to do with circumcision. The earliest clear medical
description of haemophilia is probably in 1803, and the name 'haemophilia' is
first found in a dissertation by Hopff in 1828. Haemarthroses were not clearly
described in relation to haemophilia until 1890, because before that they were
thought to be rheumatic manifestations. The first female haemophiliac, from a
first-cousin marriage, is believed to be that recorded by Treves in 1886; and
the diagnostic triad of lifelong, male bleeding, transmitted by females, is first
really brought out in the monumental study of Bulloch and Fildes in 1911.
They analysed the entire previous literature on abnormal bleeding and sorted
out the reports they thought were probably to do with haemophilia, and
published a large number of family trees. We all know about Queen Victoria,
who had a haemophilic son, Leopold, born in 1853, and two carrier daughters
who transmitted the abnormal gene to the Royal Houses of Spain and Russia.
Defective blood clotting in haemophilia was first noted, I think, by Wardrop
in 1835, yet haemophilic blood was normally clotted by thrombin by Addis in
1910 and the normal prothrombin time was recorded by Quick in 1935.
I always regard that as the beginning of the modern period in the study of
haemophilia, because up to that time, although some plasma fractions were
made in the laboratories, it was thought that it was the prothrombin that was
abnormal in haemophilia. A globulin fraction of plasma was found to correct
4 Professor Ilsley Ingram FRCP FRCPath FLS (b. 1919) was Director of the Haemophilia
Centre at St Thomas' Hospital from 1956 to 1979, and Professor of Experimental
Haematology in the University of London at St Thomas's Hospital Medical School from 1972
5 These early landmarks in the history of haemophilia are detailed and referenced in Ingram G
I C. (1997) The history of haemophilia. Haemophilia 3: 5-15. idem (1976) The history of
haemophilia. Journal of Clinical Pathology 29: 469-479.
Haemophilia: Recent history
the haemophilic blood-clotting defect by Patek and Taylor in 1937, 6 so in the
1930s the modern study had begun. The term 'antihaemophilic globulin'
(AHG) was coined by Lewis, Taylor and others in 1946. 7 In 1950 Merskey
described mild haemophilia with a normal whole blood-clotting time in a
glass tube. 8 This was of great clinical importance because up until then it was
thought that if the clotting time was normal, the person could not have
haemophilia. But we know that mild haemophiliacs do indeed have serious
post-traumatic bleeding, for instance if they are inadvertently operated on
without proper preparation.
From 1951 onwards there were early assay methods for factor VIII,
particularly Merskey and Macfarlane [in Oxford] , and Graham and others in
America. 9 Roman numerals were first used to designate clotting factors by a
committee chaired by Wright in 1962; 10 and the immunological detection of
factor VIII was begun by Ratnoff and others in 1971, who showed that
haemophilic plasma, although it contained no factor VIII activity, reacted with
a rabbit antibody to human factor VIII. I expect that subsequent speakers will
say more about the immunological side, because that has developed greatly
since I retired in 1979. An international standard for factor VIII clotting
activity was developed in the 1960s by the Biological Standards Division of
the National Institute for Medical Research; and the Division began to
distribute working standards to clinical laboratories. 13
Von Willebrand's disease was distinguished from haemophilia by von
Willebrand in 1926 and by Minot in 1928, and was shown to affect both sexes
6 Patek A J, Taylor F H L. (1937) Hemophilia II. Some properties of a substance obtained
from normal human plasma effective in accelerating the coagulation of hemophilic blood.
Journal of Clinical Investigation 16: 113-124.
7 Lewis J H, Tagnon H J, Davidson C S, Minot G R, Taylor F H L. (1946) The relation
of certain fractions of the plasma globulins to the coagulation defect in hemophilia.
8 Merskey C. (1951) Haemophilia associated with normal coagulation time. British Medical
Journals. 906-912. See biographical note 35 below.
9 Merskey C, Macfarlane R G. (1951) Female carrier of haemophilia: a clinical and laboratory
study. Lancet i: 487-490. Graham J B, Penick G D, Brinkhous K M. (1951) Utilization of
antihemophilic factor during clotting of canine blood and plasma. American Journal of
Physiology 164: 710-715.
10 Irving Wright, Professor of Internal Medicine at Cornell, New York, chaired the
International Committee on Blood Clotting Factors, which later became the International
Committee on Haemostasis and Thrombosis in 1965. See Wright I S. (1962) The nomenclature
of blood clotting factors. Thrombosis et Diathesis Haemorrhagica 7: 381-388.
11 Zimmerman T S, Ratnoff O D, Littell A S. (1971) Detection of carriers of classic
hemophilia using an immunologic assay for antihemophilic factor (factor VIII). Journal of
Clinical Investigation 50: 255-258.
12 The patient's plasma and the antibody diffuse in a gel: where they meet, an opaque line forms
if the plasma contains a substance 'recognized' by the antibody.
13 See Dr Derek Bangham's contribution on page 20.
Haemophilia: Recent history
and to have a long bleeding time. Reduced levels of factor VIII were also
found in von Willebrand's disease by Alexander and Goldstein in 1953, and by
Larrieu and Soulier in 1953. 15
In 1944 Pavlovsky described the mutual cross-correction of two
haemophilic bloods 16 and this led to the identification of factor IX deficiency
with identical clinical manifestations to haemophilia. Then Macfarlane and
Biggs developed the thromboplastin generation test which allowed clinical
laboratories to distinguish the two conditions. 17 It was largely on that basis, I
understand, that the system of 'Haemophilia Centres' was set up in Britain, the
initial purpose being to separate the diagnosis of haemophilia from that of
Christmas disease (factor IX defect), 18 in readiness for the time when different
specific treatments would be available. Topical treatment with Russell's viper
venom [Stypven], which was found to clot haemophilic blood, at the dilution of
one in a million, was identified by Macfarlane in 1934. 19 Use of blood
transfusion, interestingly, dates back to the work of Lane in 1840, who
effectively administered the blood of someone he described as 'a stout young
woman' to a boy, known to have bled abnormally, who had been inadvertently
operated on, and bled and bled.
1 See Willebrand E A von. (1926) Hereditare pseudohemofili. Finska Ldkaresdllskapets
Handlingar 68: 87-112. Minot G R. (1928) Familial hemorrhagic condition associated with
prolongation of bleeding time. American Journal of Medical Science 175: 301-306.
15 Alexander B, Goldstein R. (1953) Dual hemostatic defect in pseudohemophilia. Journal of
Clinical Investigation 32: 551. Larrieu M J, Soulier J P. (1953) Deficit en facteur
antihemophilique A chez une fille, associe a un trouble du saignement. Revue d'hematologie 8:
361-370. idem Differentiation of hemophilia into 2 groups: study of 33 cases. New England
Journal of Medicine 249: 547-553.
16 Professor Ilsley Ingram added: 'Both having prolonged clotting times but the mixture
clotting normally, showing that the samples corrected each other and must therefore have had
different deficits, each able to provide what the other lacked.' Letter to Dr Daphne Christie, 13
March 1999. See Castex M R, Pavlovsky A, Simonetti C. (1944) Contribucion al estudio de la
fisiopatogenia de la hemofilia. Medicina Buenos Aires 5: 16-24. Pavlovsky A (1947)
Contribution to the pathogenesis of hemophilia. Bloodl: 185-191.
17 Macfarlane R G, Biggs R. (1953) Thrombin generation test: application in haemophilia and
thrombocytopenia. Journal of Clinical Pathology 6: 3-8. Biggs R, Douglas A S. (1953)
Thromboplastin generation test. ibid. 23-29. Biggs R, Douglas A S, Macfarlane R G. (1953)
Formation of thromboplastin in human blood. Journal of Physiology 119: 89-101.
18 See Biggs R, Douglas A S, Macfarlane R G, Dacie J V, Pitney W R, Merskey C, O'Brien J R.
(1952) Christmas disease: a condition previously mistaken for haemophilia. British Medical
Journal u: 1378-1382.
19 Macfarlane R G, Barnett B. (1934) The haemostatic possibilities of snake venom. Lancet ii:
985-987. idem On the relative potency of certain snake-venoms to coagulate haemophilic
blood. Proceedings of the Zoological Society A:-. 977-978. Macfarlane R G. (1965) Russell's viper
venom, 1934-64. Oxford Medical School Gazette 17: 100-115.
20 Lane S. (1840) Haemorrhagic diathesis. Successful transfusion of blood. Lancet i: 185-188.
See also Ingram G I C. (1995) Mr Lane and the blood of a stout young woman. Haemophilia
Haemophilia: Recent history
In 1931 Macfarlane, who reviewed the previous treatments offered for
haemophilia, clearly recognized that human blood transfusion was the only
effective systemic treatment. Freeze-dried fractions made from human blood
were developed in the 1950s by Kekwick and Wolf, Soulier, Blomback and
others, 22 and then Dr Bidwell in 1954 introduced the fractions from ox and pig
plasma. 23 In 1965 Judith Pool introduced cryoprecipitate. 2 This was a major
clinical advance because of the convenience of the smaller volume for
administration and because it could be stored frozen. Use of antifibrinolytic
drugs to spare factor VIII doses was introduced by Walsh in 1 97 1 in connection
with dental extractions, 25 and the use of l-deamino-8-D-arginine vasopressin
(DDAVP) in mild haemophilia and von Willebrand's disease by Mannucci in
I will add that in the UK the Haemophilia Society had its roots in the
1930s, curiously when Macfarlane and J B S Haldane worked together on the
interesting parallel between the inheritance of haemophilia and red/green colour
blindness. 27 That was probably the first time in Britain that haemophiliacs
came together and so met one another. In 1950 the British Haemophilia
Society, which had at first grandly been called the International Haemophilia
21 Macfarlane R G. (1931) Haemophilia: a short survey. St Bartholomew's Hospital Journal
22 Kekwick R A, Wolf P. (1957) A concentrate of human antihaemophilic factor — its use in six
cases of haemophilia. Lancet'v. 647-650. Soulier J P, Gobbi F, Larrieu M J. (1957) Separation
du fibrinogene et du factuer antihemophilique A Revue d'hematologie 12: 481-496. Blomback
B, Blomback M, Nilsson I M. (1958) Note on the purification of human antihemophilic
globulin. Acta Chemica Scandinavica 12: 1878.
23 Macfarlane R G, Biggs R, Bidwell E. (1954) Bovine antihaemophilic globulin in the
treatment of haemophilia. Lancet'v. 1316-1319. Bidwell E. (1955) The purification of bovine
antihaemophilic globulin. British Journal of Haematology 1: 35 and 386.
24 Professor Judith Pool reported that on slowly thawing frozen plasma, much of the factor
VIII activity remained with the fibrinogen sludge which was slow to re-dissolve, the so-called
'cryoprecipitate'. This could be spun down, re-frozen for storage and finally reconstituted for
administration in a small volume of saline. For details see Pool J D, Shannon A E. (1965)
Production of high-potency concentrates of antihemophilic globulin in a closed bag system.
New England Journal of Medicine 273: 1443-1447. See also Sibinga C S. (1996) Emile Remigy
and the discovery of anti-haemophilic activity in cryoprecipitate. Haemophilia 2: 56-60.
25 Walsh P N, Rizza C R, Matthews J M, Eipe J, Kernoff P B A, Coles M D, Bloom A L,
Kaufman B M, Beck P, Hanan C M, Biggs R. (1971) Epsilon-aminocaproic acid therapy for
dental extractions in haemophilia and Christmas disease: a double blind controlled trial.
British Journal of Haematology 20: 463-475.
26 See Cash J D, Gader A M A, Da Costa J. (1974) The release of plasminogen activator and
factor VIII to lysine vasopressin, arginine vasopressin, l-deamino-8-D-arginine vasopressin,
angiotensin and oxytocin in man. British Journal of Haematology 27: 263-264. Mannucci P M,
Ruggeri Z M, Pared F I, Capitanio A (1977) l-deamino-8-D-arginine vasopressin: a new
pharmacological approach to the management of haemophilia and von "Willebrand's disease.
27 See Bell J, Haldane J B S. (1937) Linkage between genes for colour-blindness and
haemophilia in man. Proceedings of the Royal Society B 123: 1 19-150.
Haemophilia: Recent history
Society, was registered as a charity; the World Federation of Hemophilia was
started in 1963.
Haemophiliacs have always been very generous in giving their plasma for
experimental work as a quid pro quo for being looked after. I think that this is a
very interesting example of the way that affected people and their doctors
worked together for mutual benefit.
Lee: I would like to pursue some of the things you brought up there. When we
were talking with Dr Biggs last week, 28 she was laying great emphasis on the
thromboplastin generation test 29 as the point at which diagnosis was possible.
Would you agree with that?
Ingram: Yes, in Britain, I think that was of great importance. In America, at
Chapel Hill, Brinkhous and Graham developed the partial thromboplastin
time, 30 which wasn't so good at distinguishing deficiencies of factors VIII and
IX, but could be adapted to do so by the use of appropriate plasmas. But the
great thing about the thromboplastin generation test was that the reagents were
made from normal plasma, so that you didn't have to have the haemophilic
blood there to show whether or not it was corrected. I will go back to the time
where the mutual correction of two apparently haemophilic plasmas led to the
realization that there was more than one defect, because, after all, this is
analogous to the general biological principle of identification from type
specimens. There you had a type specimen of haemophilic blood and then you
saw whether other bloods would correct it or not. Fortunately, the
thromboplastin generation test side-stepped that and made it unnecessary for
all laboratories to have samples of both haemophilic and Christmas disease
plasma always on hand.
Lee: And that mutual correction, when we were talking with Dr Biggs, 31 she
said was just done by accident.
28 See note 2 above.
29 See note 17 above.
30 Langdell R D, Graham J B, Brinkhous K N. (1950) Prothrombin utilization during
clotting: comparison of results with 2-stage and 1 -stage methods. Proceedings of the Society for
Experimental Biology and Medicine 74: 424. Langdell R D, Wagner R H, Brinkhous K M.
Effect of antihemophilic factor on one-stage clotting tests: presumptive test for hemophilia
and a simple one-stage antihemophilic assay procedure. Journal of Laboratory and Clinical
31 See note 2 above.
Haemophilia: Recent history
Ingram: I think it was, yes. It was a bit of serendipity.
Lee: When the thromboplastin generation test was described and it was
possible to differentiate, who was using it? Was it just the very specialized
centres, or was it more widespread?
Ingram: I think it gradually spread, although perhaps people who hadn't seen
it done found it rather fiddly to do from written instructions, but it was
becoming more widely used.
Lee: I think it might be an appropriate time to talk about differentiation of
factor VIII and factor IX. Dr Rizza, remind us about Christmas disease.
Dr Charles Rizza: 32 Can I go back to what Professor Ingram said? I think of
the serendipity when Stephen Christmas first came to Oxford: I think it was
John Poole 33 who did the mixing experiments. He took haemophilic blood and
mixed it with Stephen Christmas's blood and, lo and behold, it was corrected,
and they thought, 'What is going on here? There is something different'. That
was how it all began. But Stuart Douglas, I think, was there at the time and that
what encouraged him to look further and use the thromboplastin generation test
Professor Stuart Douglas: 34 I want to comment on the contribution of
experiments on mixing of bloods from two haemophiliacs. We should
32 Dr Charles Rizza FRCPEd (b. 1930) was MRC Clinical Research Fellow at the Blood
Coagulation Research Unit in Oxford between 1958 and 1961, working with Dr R G
Macfarlane and Dr Rosemary Biggs. He was awarded an MD from the University of St
Andrews in 1962 and received the University Gold Medal for his thesis 'Conditions affecting
the level of antihaemophilic globulin (factor VIII) in the blood.' He was Consultant
Physician at the Oxford Haemophilia Centre from 1966 to 1993, and Director of the Centre
from 1977 to 1993. He was Clinical Lecturer in Haemophilia at the University of Oxford
between 1967 and 1993
and Chairman of the United Kingdom Haemophilia Centre Directors Organization from
1987 to 1990.
33 John Poole was a registrar in Oxford in 1951. See also note 41.
34 Professor Stuart Douglas FRCP FRSEd (1921-1998) qualified in medicine at Glasgow in
1944. He won a Medical Research Council fellowship to work in the Blood Coagulation
Research Unit in Oxford where he and others devised the thromboplastin generation test (see
note 17 above). His main interest was in the study of blood coagulation and bleeding, and later
problems of thrombosis. He was Professor of Medicine in Aberdeen, from 1970 to 1985
Haemophilia: Recent history
recognize Clarence Merskey, a research fellow from South Africa working in
Oxford in 1949, for introducing the habit of mixing blood from two
haemophiliacs. He pointed out that there were at least two grades of
haemophilia: one severe and one mild. 3 Addition of a small amount of plasma
from the mild patient would give some correction of the plasma-clotting time
of the severe haemophiliac,
but not as effectively as normal plasma. This mixing became part of the
laboratory 'work up' of a new suspected bleeder. A test for haemophilia was
failure to correct the recalcification time of a known haemophilic plasma as
effectively as normal plasma. 37
I thought of the Oxford-taught investigators, John Poole was the first to
find cross-correction. 38 I did not know that John O'Brien had found this at an
earlier date. 39
Ingram: I think even before the mixing in Oxford someone did it in South
Douglas: I think if you look, John Poole didn't actually describe that
phenomenon until the Christmas disease paper was published, but I think if
you talk to him, you'll find that he did it many years earlier. Ilsley Ingram in
35 Dr Clarence Merskey FRCP (1914-1982) worked with Biggs and Macfarlane from 1949 to
1951 at the Radcliffe Infirmary, Oxford, where he developed his coagulation expertise and
made valuable contributions to the study of haemophilia. In New York he collaborated closely
with Alan Johnson (mentioned later in the meeting) devising tests for measuring fibrin
degradation products. See also notes 8, 9 and 36.
36 Merskey C. (1950) The laboratory diagnosis of haemophilia. Journal of Clinical Pathology
3: 301-320. See also note 8 above.
37 Small amounts of normal plasma and of the patient's plasma are added to citrated plasma
from the known haemophiliac, and the clotting times after recalcification are recorded. Very
small proportions of normal plasma will shorten the calcium-clotting time of haemophilic
plasma almost to normal. If similar proportions of the patient's plasma fail to do so, he
presumably has haemophilia. See Biggs R, Macfarlane R G. (1953) The coagulation defect in
haemophilia. In Human Blood Coagulation and its Disorders, ch. XV. Oxford: Blackwell
Scientific Publications, 227-231, 348.
38 See notes 16 and 41.
39 Professor Stuart Douglas wrote: 'I had thought the first assessment in Oxford of Stephen
Christmas's blood was a sample collected by me from London at the request of John Dacie and
Bob Pitney in 1952. I am willing to be proved wrong.' Letter to Dr Tilli Tansey, 24 July
op. cit. note 16 above.
41 Poole J C F. (1953) A haemorrhagic state resembling haemophilia. Lancet i: 122. op. cit.
note 18 above.
Haemophilia: Recent history
his introductory remarks also mentioned Mannucci in relation to the use of
DDAVP in mild haemophilia. 42 There was an important British contribution
which led to the work by Mannucci in 1977. You [Ingram] showed that the level
of factor VIII in normal blood could be raised by injections of adrenaline 43
and you [Rizza] showed a rise in factor VIII after exercise. 44 John Cash and his
colleagues in Edinburgh showed that these responses could not be totally
prevented by OC and (3 receptor blockers and the possibility was raised of an
involvement of the hypothalamic-pituitary axis as a secondary pathway. 5 The
only neuropeptide available for human prescription was vasopressin -
(ADH) - and they gave this to themselves, and found a factor VIII response;
side-effects were too troublesome for clinical practice (vasoconstriction, and
powerful contractions of the uterus and gastrointestinal tract). They found that
the synthetic analogue desmopressin [DDAVP] was as active in raising factor
VIII (and von Willebrand's factor) as the natural antidiuretic hormone.
Clinicians in their Haemophilia Centre in Edinburgh had ethical doubts about
trying this in haemophilia. The clinical value was then established by Mannucci.
Ingram: Desmopressin [DDAVP] is a synthetic analogue of vasopressin
[antidiuretic hormone] from the hypothalamic/posterior pituitary axis; it has
the advantage that it does not stimulate bowel contraction or raise blood
pressure like the normal hormone, so that it can be given virtually
symptomlessly, but it does raise factor VIII between two- and four-fold in the
normal subject and proportionally in mild haemophilia but not in severe
haemophilia. It has also found a place in treating von Willebrand's disease and
Lee: We still use it by preference in people with mild disease, rather than
clotting factor concentrates, and recently there is a formulation which comes as
a nasal spray which people are using for home treatment as well. Charlie, can we
get back to Christmas disease and 1952?
2 op. cit. note 26 above.
3 Ingram G I C. (1961) Increase in antihaemophilic globulin activity following infusion of
adrenaline. Journal of Physiology 156: 217-224.
Rizza C R. (1961) Effect of exercise on the level of antihaemophilic globulin in human
blood. Journal of Physiology 156: 128-135.
45 Ingram G I C, Vaughan Jones R. (1966) The rise in clotting factor VIII induced in man by
adrenaline: effect of a- and (3-blockers. Journal of Physiology 187: 447-454. Gader A M, Da
Costa J, Cash J D. (1974) The effect of propranolol, alprenolol and practolol on the
fibrinolytic and factor VIII responses to adrenaline and salbutamol in man. Thrombosis
46 Mannucci P M, Ruggeri Z M, Pared F I, Capitano A. (1983) op. cit. note 26 above.
Haemophilia: Recent history
Rizza: Dr Bidwell is here. She is the one to answer that.
Dr Ethel Bidwell: 47 I couldn't think what everybody was so interested in, in
1952, and they weren't at all interested in what I was doing. Then people
slowly explained to me about this Christmas disease and then I realized.
Rizza: I think the trouble with Christmas disease in 1952 was that, as for
haemophilia, there was no therapy. There was no treatment apart from plasma
transfusion, giving moral support and holding the patient's hand. When the
NHS began 50 years ago, that's just when I started to study medicine, there
was no therapy, although as Ilsley said, the antihaemophilic globulin had been
recognized as being the important constituent of plasma which haemophiliacs
lack. Since 1941, Cohn had been fractionating human plasma into its various
constituents, 48 so rather than giving the patient the whole plasma the different
patients were given only the fraction they required. It was soon shown that
Cohn's fibrinogen fraction was contaminated with factor VIII and began to
be used in a limited way in the late 1940s and early 1950s for the treatment
Bidwell: Certainly for a long time after that we weren't still sure that factor
VIII and fibrinogen were not modified forms of the same thing. One of the
few purely academic things that I was ever involved in was electrophoretic
separation, not from the point of view of preparation of factor VIII, but just to
show you could get them apart.
Lee: Dr Bidwell, tell us when you first got involved in making treatment for
7 Dr Ethel Bidwell (b. 1919), an experienced enzyme chemist, joined Macfarlane in Oxford
in 1950 and in 1952 started a study of plasma concentration and selective extraction of factor
VIII. By 1953 she was producing a concentrated bovine factor VIII 8000 times as strong as
normal human plasma. In 1959 she held a full time MRC appointment in the newly opened
MRC Blood Coagulation Research Unit in the grounds of the Churchill Hospital,
Headington, Oxford, and concerned herself with the preparation of human coagulation factors.
See Report of the Medical Research Council for the Year 1958-1959. London: HMSO, 111. Her
research assistant, Ross Dike (see biographical note 177 below), joined the team in 1954. Dr
Bidwell retired in 1981. See also notes 60 and 62 below.
8 Cohn E J. (1941) Properties and functions of plasma proteins with consideration of methods
for their separation and purification. Chemical Reviews 28: 395-417. idem (1947) Separation of
blood into fractions of therapeutic value. Annals of Internal Medicine 26: 341-352.
9 Human factor VIII was first available in 1957, see note 3 above. For animal factor VIII, see
page 13 below. Minot G R, Taylor F H L. (1947) Hemophilia: the clinical use of
antihemophilic globulin. Annals of Internal Medicine 26: 363-367. Alexander B, Landwehr G.
(1948) Studies of hemophilia. II. The assay of the antihemophilic clot promoting principle in
normal human plasma with some observations on the relative potency of certain plasma
fractions. Journal of Clinical Investigation 27: 9-18.
Haemophilia: Recent history
Bidwell: I went to Oxford in 1950, not because I had an interest in blood
coagulation, but because Macfarlane worked on gas gangrene. I worked for seven
years for the Wellcome Foundation, during the war, on toxins of anaerobic
bacteria involved in gas gangrene and later on tetanus toxin. Macfarlane wanted
someone to work on nothing to do with blood coagulation. I got pretty
browned off to find nobody was interested in what I was doing [they were
involved in the discovery of factor IX deficiencies] . They realized that I was
restless, because I didn't want to work all on my own in a corner doing
something nobody was interested in. So he said to me, 'Well we have got
nothing to treat these haemophilic patients with, would you like to have a go at
seeing if you can make something from animal blood?'. So that's how I got
started in 1952.
Lee: Which animals did you choose first of all?
Bidwell: Animals that were slaughtered in a slaughterhouse. I think the first
thing was the bovine blood. When I got involved, it was done by the
slaughterhouse men and they were very helpful, very kind. They wanted the very
best for me. They wanted me to have the animals that had won all the rosettes
at the shows, but ancient old cows were much better. I went down to the
slaughterhouse on my Vespa motorbike and I came back with a large glass
container. I got concerned lest I tipped off my motorbike and tipped blood on
Lee: How much blood would you be collecting?
Bidwell: About a gallon. People don't realize that plastics were only just
coming in. It cost me about the equivalent of a week's wages to buy a plastic
container to put the blood in so that it wouldn't break on the road to Oxford.
Lee: What year are we talking about?
Bidwell: 1952. As I say, I had worked on gas gangrene toxins, Welchii toxins,
at the Wellcome Foundation and I put that sort of knowledge to use, but I was a
very pure chemist, who went round bleating, 'What is a cell?' to my colleagues.
I just had to make use of what was available. There were no refrigerated
centrifuges. We had to cool them with dry ice and so on. The Blood
Transfusion Centre was three miles away and they didn't even have a centrifuge
Haemophilia: Recent history
to spin their bottles. They used to have to come to us if they wanted to prepare
blood. People just don't realize the things that weren't there.
One of our major problems was sterilization, because the properties of the
factor VIII were such that it wouldn't go through the usual filter media, and
that's why in the beginning we used to just hopefully give it a high-speed spin
and put it in a quartz tube and irradiate it; it wasn't really sterile.
Lee: When did you have the first lot of treatment material that you actually
were prepared to use?
Bidwell: It was about 1954 when we started to use it for patients requiring
tooth extraction, knowing that they were likely to bleed to death if we failed.
Then in the autumn of 1954, we were called to Norwich for a patient who
worked in a gun shop and he had got shot by mistake by a customer who was
trying out a gun! So we went up there and to our horror when we tried the bovine
factor VIII, the patient had the most awful anaphylactic reactions. We couldn't
understand this; we hadn't had this sort of reaction before. I am not medical
myself, so I was chatting away to the technicians while the medical people were
having talks at a distance and the technicians whispered to me that this patient
about ten days earlier had been given an Italian preparation which I vaguely
thought was from bovine material. So I went to Macfarlane and whispered,
'Can I speak to you?' and I told him about this and of course his face changed
because he realized the significance - the patient had been sensitized to the
bovine material. Macfarlane and Biggs had to go back to Oxford, and I and a
Canadian called Danny Bergsagel, a medical man who was working with them,
stayed behind and eventually the patient was moved to Oxford in an RAF
plane. That was the first time I had flown and I was sitting on the floor of this
plane while a nurse was putting a drip up. I got back to Oxford, the patient
continued to have reactions to the bovine material and I can remember at the
end of that week going to Macfarlane and saying, 'There's nothing I can do, can
I try pig?' and he said, 'Well, go on'.
The first pig we used was from an animal that was being slaughtered in the
next village on the Sunday morning. Ross Dike 50 had just joined me and I rang
him up. That's when we started work and by Wednesday we were treating that
patient with a course of porcine antihaemophilic globulin. They wouldn't let
you do that these days.
50 See Ross Dike's contributions later in this meeting and biographical note 177 below.
Haemophilia: Recent history
Lee: No, that's right. One of the things that I hadn't quite understood, and it
came out when we were speaking with Dr Biggs 51 and again here, is why did
people push to use animal plasma. I think I am right in saying that Macfarlane
had made the calculation of how much plasma was needed from human blood
in the United Kingdom to treat the people with haemophilia and he came up
with the calculation that it was absolutely impossible; so he therefore said we
must use animals. Isn't that right?
Ingram: Yes, that's right.
Bidwell: Not only that. Again I emphasize this was before the advent of
plastic, which made all the difference practically.
Dr Peter Jones: 52 If we can put this into context, this discovery and the large
scale manufacture, I think later by Maws, 53 of the animal products brought
treatment particularly to people who had to have major surgery. In the 1960s,
when I started in haemophilia care, the major operation wasn't reconstructive
surgery, it was for peptic ulceration with partial gastrectomies, and
pyloroplasties and vagotomies. There was simply not enough human factor
VIII in the United Kingdom to treat more than one patient at a time, and so
we had to turn to the animal products and they were terrific. We used to go for
pig first, because we thought it was least antigenic and least likely to cause
thrombocytopenia. The antihaemophilic effect lasted for something like five,
six, seven, and if you were lucky, eight days, and then we used to change to
bovine and that would last a similar period. We watched the platelet count but
never had a clinical problem. Last of all we'd top up with human factor VIII if
the patient hadn't healed. But that was the position. We used to have to ring
round to Oxford and to Edinburgh, and to our colleagues in London to get
enough human factor VIII for one major surgical operation at a time. So the
animal products were life-saving very early after their introduction.
51 op. cit. note 2 above.
52 Dr Peter Jones FRCP (b. 1937) is Consultant Paediatrician at the Royal Victoria Infirmary,
Newcastle upon Tyne. He is Director of the Newcastle Haemophilia Centre and an Executive
Member of the World Federation of Hemophilia. In 1981 he received the Gold Medal
(Macfarlane Award) of the Haemophilia Society. He has published extensively on
haemophilia and on AIDS, and is the author of Living with Haemophilia, 4th edition. Oxford:
Oxford University Press.
53 It had been arranged that the firm of Maws & Son Ltd should take over the responsibility
from Bidwell (see note 47 above) for preparing concentrates of animal factor VIII.
Haemophilia: Recent history
Ingram: I have here a copy of the surgical course of a patient who had an
abdomino-perineal excision in October 1959 and who had treatment with ox
and pig, and human factor VIII. 54
Lee: Another point that Dr Biggs made was that you [Bidwell] didn't use
sheep and there was a reason for that.
Bidwell: There were two reasons. One was that sheep were very woolly, so it
would have been extremely difficult to collect blood that didn't clot as fast as
you looked at it. 55 The other is that the relationship between sheep and cows
was close enough to get a cross reaction.
Rizza: Dr Bidwell mentioned the horrendous reaction that the man in Norwich
had, 56 but of course patients nearly always had reactions as the course of therapy
went on and you had to watch for this and the patients told some lovely stories.
'Why is it, doctor, I always see stars in front of my eyes when this stuff goes in?'
and we didn't know why they were seeing stars. In retrospect the suggestion is
that it may have been platelet clumps going through the retina, because the
AHG clumped the platelets and the platelets disappeared from the blood as a
consequence. One ended up sometimes with the patient at risk of bleeding from
thrombocytopenia, although his haemophilia was better. It was very, very
interesting. James Matthews 57 and I had many a worrying time with patients
going on to second courses of treatment and wondering what would happen
Bidwell: Do you remember the terrible cysts that the patients used to have? As
I say, I am not medical, I was told that according to strict anatomy they
shouldn't have had those, because there shouldn't have been a track but there
obviously were and they were frightful.
5 Copy prepared for the meeting by Ilsley Ingram, taken from Christie T H, Graham-Stewart
C W, Ingram G I C (1960) Abdomino-perineal resection of the rectum in a haemophiliac.
Thrombosis et Diathesis Haemorrhagica iv: 224-234, page 229.
55 The blood on the wool would coagulate very quickly.
5 This refers to the anaphylactic reaction after treatment with bovine factor VIII of the patient
with a gun shot wound described earlier by Ethel Bidwell.
57 Dr James Matthews contributes later in the meeting, see biographical note 110.
Haemophilia: Recent history
Rizza: This is the awful thing with haemophilia bleeding of course. It can track
anywhere. It can destroy soft tissue, it can destroy even bone, because of the
pressure it can exert in a confined space.
Your [Bidwell] factor VIII was excellent material and so was the Maws
material and the Crookes, but the problem we had was getting it into solution.
It took an hour sometimes or more, shaking bottles, and you had to be careful
not to shake too hard, because if you got a froth the powder would never
dissolve, because the factor VIII would sit in clumps on the bubbles and
wouldn't go into the water. This is one of my recollections, sitting for two or
three hours shaking. In fact, all of the department used to be involved in this. If
it was major surgery which was being undertaken, you made up numerous
bottles and you passed them round to technicians, secretaries, research workers
and they'd all sit there at tea time drinking their tea and shaking their bottles.
Dr Brian Colvin: 58 1 want to add a little bit to what Peter [Jones] said about
peptic ulceration and haemophilia. I still look after a patient who had, I think,
bovine or porcine factor VIII in 1961 in Oxford and it's important to
appreciate that people not only got hold of this material, but also referred
patients to Oxford. For many years, even after my interest began, people were
being referred to Oxford for treatment and to have their lives saved. It's
significant perhaps that 40 years later some of these people are still walking the
planet, who certainly wouldn't be doing so otherwise.
Perhaps while I have the microphone, I could add a little tiny anecdote to
Professor Ingram's presentation. Treves's description of the haemophilia scene
in 1886 in the Lancet® relates to an East End family and concerns a young girl
called Florence. I never saw her, but her daughter, Edith, broke her hip in a
strike in 1978 and couldn't be accommodated at The London so she was sent to
the Royal Free to be operated on. This lady was also probably a true
haemophiliac and had four sons, all of whom had haemophilia, and the last of
those sons died last month. So we have a direct link to Treves's description in
1886. Some years ago our district treasurer asked me how long we had been
treating haemophilia at the Royal London Hospital and I was able to tell him
that it was since 1886, which dealt with the argument.
58 Dr Brian Colvin FRCP FRCPath (b. 1946) is Assistant Warden at St Bartholomew's and The
Royal London School of Medicine and Dentistry. He has been Consultant Haematologist and
Haemophilia Centre Director at The Royal London Hospital since 1977 and Director of
Postgraduate Medical and Dental Education at the Royal Hospitals Trust since 1996. He is a
Member of the British Society for Haematology and has published many papers on the
management of haemophilia.
,9 Treves F. (1886) A case of haemophilia, pedigree through five generations. Lancet ii:
Haemophilia: Recent history
Lee: Dr Rizza, we just heard then how people were sent to Oxford to have
treatment. Tell us about the little boy.
Rizza: Oh, the little boy with Christmas disease. I think he was the first person
to receive Dr Bidwell's factor IX. I was lucky enough to be working with Dr
Macfarlane and Dr Biggs in 1959-60 and I used to write home to friends and
colleagues, telling them episodes about my personal life as well as my working
life. I told them what I was up to and what was happening at the Centre, what
was being done in the way of research. It's a thing you daren't do nowadays.
You keep your notebooks shut; nowadays you must not tell anyone what you are
doing. Everything was so relaxed in those days, you didn't mind telling people
what you were doing in the way of research. You didn't expect them to steal
your ideas or results. I wrote and I said that Dr Bidwell was being successful
with the factor IX concentrate and that Dr Biggs had made an assay, and that
soon this concentrate would be available. Promptly, Dr Biggs got a telephone
call from Dundee where I had come from, asking if she could take on the care
of a little boy of four, who had had a venepuncture in the antecubital fossa and
for some reason or other had developed a haematoma at the site of puncture. 1 1
got huge. It got infected and he ended up with osteomyelitis of the radius and
he was in a very bad way. He was obviously very frightened, in great pain. He
was referred to Oxford to be looked after by Professor Trueta, 61 who was
Professor of Orthopaedic Surgery then, a paediatrician called Dr Victoria
Smallpeice and Dr Biggs. I remember when we unwrapped his hand, his thumb
fell off, because his thumb was gangrenous. As soon as he was admitted Trueta
said, 'This [forearm] must come off, he's very ill, he's infected', and this was
done. I remember the first dose being given. You, Dr Bidwell, were there
watching. Dr Bidwell liked to see what the junior doctors got up to with her
material, so that she knew whether it was the doctor's mishandling of the
material, rather than the material that caused the problems. The child was taken
to theatre and given factor IX, and he had to be sedated with rectal pentothal
every day because he was so frightened. But the operation went very well, the
factor IX caused no [side] reactions whatsoever, and he healed very well. I know
that boy well, because when I was up in Scotland last year I went to see him.
He's now 42 years old, he's an architect, and he tells me that he likes to play
60 See Rizza C R. (1995) The first patient to receive factor IX concentrate in the UK: a
recollection. Haemophilia 1: 201-212.
61 Professor Joseph Trueta FRCS DSc (1897-1977). Following a distinguished career during
the Spanish Civil War was surgeon in charge of the accident service at the Radcliffe Infirmary
in Oxford in 1942 and Nuffield Professor of Orthopaedic Surgery at Oxford from 1949 to
1965. He was succeeded by Professor Robert Duthie (see biographical note 106). See Strubell
M, Strubell M. (1980) Trueta: Surgeon in war and peace. (Translated memoirs) London: Victor
Haemophilia: Recent history
golf. He has only one hand, of course. He did away with his prosthesis very
early on, because he found the artificial arm more of a nuisance than a benefit,
and he plays one-handed, right-handed golf.
Bid well: I remember his ginger hair, bright, bright. I had been putting together
enough factor IX for some sort of cold operation such as tooth extraction on an
adult, when you [Rizza] came to me with this story, and, of course, having
worked with gangrene organisms, it put terror into me. I have never been so
frightened in my life.
Rizza: It's sad to say that the man you were saving the factor IX for had
haemorrhoids and had to have his operation postponed for several months.
Bidwell: I didn't know what he suffered from.
Rizza: It's a bit sad, because he was the man who came and gave us blood every
month for Dr Biggs to develop the factor IX assay, so he thought he was getting
the assay developed for himself and you were making factor IX for his surgery.
He, in fact, was a very understanding man. The only point that we haven't
mentioned is that the development of factor IX went hand in hand with the
development of good assays, because you didn't know what you were making
without good assays and you can't do anything without good assays.
Bidwell: We didn't have access to human plasma for a good long while after
that and it was decided to see if we could get any factor IX from what they
were throwing away at Elstree, at the end, when they had taken out albumin
and gammaglobulin, and factor VIII, which was everything they made. Of
62 At that time, the large-scale fractionation of plasma was carried out at the Blood Products
Laboratory of the Lister Institute at Elstree by the ether process of Kekwick and Mackay
(Kekwick R A, Mackay M E. (1954) The separation of protein fractions from human plasma
with ether. Medical Research Council Special Report Series No. 286. London: HMSO). This
yielded, as a by-product, a yellowish, green, greasy residue which was rich in factor IX and it was
with this that Dr Bidwell and her assistant, Ross Dike, used to extract factor EX. Dr Bidwell
wrote: 'I am not sure why Kekwick and Mackay did not use Cohn's fractionation method using
ethyl alcohol, but it is possible a patent covered the latter. It is a great tribute to the skills of the
early Blood Products Laboratory staff that the place did not explode or burn down. ...I mention
in the meeting that my earliest starting material for preparing factor IX was the final residue
from this process. But the first fraction from the process was a concentrate of factor VIII, which
was supplied from Elstree to clinicians in need. ...Leon Vallet worked at Elstree in getting this
into production and Dr Snape who worked with me at Oxford, is in charge there now.' Letter to
Dr Daphne Christie,
28 March 1999.
Haemophilia: Recent history
course, there was a mess with what they threw away, and that was what we used
for our factor IX, the first type of factor IX.
Lee: You were just talking about the importance of good assays and you are
talking now about making the concentrates really rather more formalized. When
did standardization start, and having standards for assays? When did
standardization become used either for assays themselves or for assaying the
material that was being made? When was it realized that that was important?
Dr Derek Bangham: 63 During the 1960s we [in the Division of Biological
Standards, National Institute for Medical Research] were constantly on the
lookout for biological substances which needed standards [reference materials]
for measurements of macromolecules in human physiology and pathology
(although not necessarily needed for legal control). Peter Walton, who had done
a PhD with Ralph Kekwick on factor VIII assays, was working with us, and
was, perhaps, the first person to prompt us that a standard was needed. He left
in the early 1960s and the Division was for some years without a haematologist.
During those years splendid papers by Macfarlane, Rosemary Biggs, Ken
Denson and others showed the variability of factor VIII concentrations during
conditions of physical activity, and variability in different people. 5 This was a
striking example where a standard was needed, for comparisons of assay results.
In 1966 I went to Oxford and introduced myself to Rosemary Biggs and
Gwyn Macfarlane. In Rosemary's office I asked her what she used as a standard.
She turned and pointed to a glass-stoppered sweet jar full of freeze-dried
bovine factor VIII preparation, and said, 'That's it'. 66 I am a medical, but was
then innocent of knowledge of blood clotting, and Rosemary, being a rather
forthright person, was a little taken aback by my proposal for a proper
standard. But when I'd described the MRC's work on biological standards, and
the possibility of establishing a WHO international standard, she immediately
63 Dr Derek Bangham FRCP (b. 1924) was Head of the Division of Biological Standards at the
NIMR from 1961 to 1972. He was later Head of the Hormones Division of the National
Institute for Biological Standards and Control (NIBSC), from 1972 to 1987.
64 Walton P L. (1962) Studies on the proteins of the blood coagulation mechanism in the
human. PhD thesis, University of London.
65 op. cit. note. 44 above. See also Denson K W. (1973) Molecular variants of haemophilia B.
Thrombosis et Diathesis Haemorrhagica 29: 217-219.
66 Dr Ethel Bidwell wrote: 'I would like to record that my seven years with the Wellcome
Foundation at Beckenham had ensured that when I had available freeze-dried bovine factor
VIII, I had at least done accelerated degradation tests showing that the material would be
sufficiently stable to serve as a standard. It was a great improvement on "pooled normal
plasma".' Letter to
Dr Daphne Christie, 28 July 1998.
Haemophilia: Recent history
agreed, and from then on was tremendously helpful. It was the start of a very
good collaboration with her, Ken Denson, Charlie Rizza and Ethel Bidwell in
setting up several standards for this field of haematology.
Some citrated plasma was freeze-dried, within four hours of its collection
at the Edgware Transfusion Centre, in ampoules in the fastidious conditions
used for biological standards. Ampoules were labelled with code numbers with
the year in which they were filled and sealed. It was first necessary to
determine, using accelerated degradation studies, if factor VIII had long-term
stability. An international collaborative study was organized to compare this
with a concentrate preparation supplied by Alan Johnson of the New York
Medical Center, freeze-dried at NIMR in ampoules coded 67/19. Each
participating laboratory was asked to assay the coded ampoule against their
own standard, or fresh human blood. 67 The results revealed that what people
called '1 ml of normal blood' varied from pools of blood, with or without
various dilutions of citrate. One chap simply used his own blood, day by day.
It was a very large and complex study, and probably the first international
study of factor VIII assays involving the world's expert laboratories. It was a
problem to sort out the huge number
By then we had been joined by a young Yugoslavian haematologist, Dr
Milica Brozovi_. She helped Joyce Skegg, our statistician, to analyse and
interpret the results, also helped by Rosemary [Biggs] . The draft report of the
study was circulated to the participants for agreement. Eventually, in 1970, the
final report was sent to the Expert Committee on Biological Standardization
of WHO, which in 1970 formally established the preparation 67/19 as the First
International Standard for factor VIII. 68 That was a significant step because
International Units of WHO have legal importance in all countries. Any
preparation for sale claiming to have factor VIII activity was obliged by law
to be labelled with those international units. Fortunately, that standard was
established just in time for the first commercial products that were licensed in
the UK, and were formally controlled in proper units. 69
67 As many as 20 laboratories participated in the study. See Bangham D R, Biggs R, BrozovL M,
Denson K W E, Skegg J L. (1971) A biological standard for the measurement of blood
coagulation Factor VIII activity. Bulletin of the World Health Organization 45: 337-351.
68 Dr Derek Bangham wrote: 'When tests for hepatitis became available, the concentrate (the
International Standard) was found to be contaminated and was promptly replaced with another
preparation established as the Second International Standard, calibrated in International
Units against the First International Standard.' Letter to Dr Daphne Christie, 27 July 1998.
69 See British Pharmacopoeia (1973) Dried human antihaemophilic fraction, 64-65.
ibid. H. Biological assay of human antihaemophlic fraction, A114-A115.
Haemophilia: Recent history
I should add, another preparation of freeze-dried whole plasma, included
in the study, was established as the British Working Standard, made available
to Haemophilia Centres all over Britain. 70 It proved to be enormously useful,
and the twentieth (replacement) working standard is now being distributed.
Lee: It's very interesting to hear how long ago it was that standardization,
which is so much part of our life, began. I want to try and change tack a little
bit, and think about the children who were having treatment. One of the things
that was said early on was that nobody really thought about what was going to
happen when these children grew up, because nobody expected them to grow up,
and it wasn't until they started having treatment that people started organizing
haemophilia care. We've got some patients in the audience and relatives of
patients, and we have also got Dr Evans and Dr Jones here, paediatricians.
Would you like to just try and take us back as far as you can and tell us about
the children and how treatment came in and the issues?
Dr David Evans: 71 I thought my brief was actually to continue with a bit of
the history after Ilsley left off. So I have got a two-part talk really. One is a
little bit of personal ramblings, which I hope will set ideas off in individuals'
minds, and perhaps get them remembering things which they may otherwise
have forgotten, and secondly, more a sort of brief run-down of things that
happened year by year afterwards. But let's start with the first bit.
I was an undergraduate at Cambridge in the early 1950s at Downing
College at a time when Sir Lionel Whitby was Master of Downing. He was, of
course, the first President of the Haemophilia Society and had an enormous
fund of information on blood disorders, which he published in his book. 72 1 1
would be nice for me to be able to say to you that as a result of this marvellous
experience of meeting Sir Lionel I was inspired with a desire to become a
haematologist, but it would not be true. All I remember about Sir Lionel was
that he'd come back from the First World War minus one leg, and with a crate
of whisky and we all respected him for that. Later in the 1950s, I was a student
70 BrozovL M. (1977) Physiological mechanisms in coagulation and fibrinolysis. British
Medical Bulletin 33: 231-238.
71 Dr David Evans FRCPEd (b. 1930) trained in paediatrics at hospitals in Carshalton and
Lewisham and in pathology at Guy's Hospital, London, before going to Booth Hall and the
Royal Manchester Children's Hospitals in Manchester where in 1966 he developed a regional
service for children with blood diseases. In 1972 he set up a Haemophilia Centre at the Royal
Manchester Children's Hospital. He retired in 1992.
72 Whitby L E H, Britton C J C. (1935) Disorders of the Blood: Diagnosis, pathology, treatment
and technique. London: J & A Churchill.
Haemophilia: Recent history
at St Thomas' where Ilsley Ingram and Roger Hardisty 73 were lecturers in
clinical pathology. I remember Ilsley Ingram giving me a tutorial, which I
can't remember much about. But he did talk about von Willebrand's disease
and that made an impression upon me, but alas it did not inspire me to become
Now, I am going to talk a little bit about blood transfusion at Manchester,
because of what we probably regard now as blood banking, which of course is
still terribly important for the early days of haemophilia care. Blood banking
was really started in the Spanish Civil War by a Basque, Dr Frederick Duran-
Jorda. He originally worked in the Public Health Department in Barcelona and
in 1936 he organized a blood transfusion service for the Catalan army during
the days of the Spanish Civil War. And this was the first time, in 1936, that
civilian blood donors had been used and their blood was stored to form a
blood bank, and this was what was original about Dr Jorda's work. 7 In 1937 it
was extended to the whole of the Spanish Army and Dr Duran-Jorda was
appointed Director of Blood Transfusion, and he gave lectures in France,
Switzerland and Czechoslovakia. In 1939 he was invited by the Red Cross to
come to England. He went to the haematology department of the Postgraduate
School and lectured to the Royal Society of Medicine. I remind you that other
Basques left Spain at the same time and that Professor Trueta, 75 who has
already been mentioned, who was later Professor of Orthopaedic Surgery at
Oxford, was another one.
In the same year, 1939, in the expectation of masses of civilian casualties
from bombing, the National Transfusion Service in the UK was set up. In 1940,
the following year, Dr Duran-Jorda came to Manchester. In 1950 he was
appointed Director of Pathology at Booth Hall Children's Hospital and this is
really why I mention him, because it was the same post that I took over from
his successor in 1966. In Manchester he would have been in touch at the Royal
73 Professor Roger Hardisty FRCP FRCPath (1922-1997) qualified at St Thomas' Hospital,
London, in 1944 concentrating on haematology and particularly the bleeding disorders. In
1957 he was appointed honorary consultant haematologist to the Hospital for Sick Children,
Great Ormond Street, London, and over 30 years built up one of the first paediatric
haematology departments in Britain. He was Professor of Paediatric Haematology at the
Institute of Child Health, London, from 1969 to 1987, and Professor Emeritus of
Haematology at the Royal Free Hospital School of Medicine, London, from 1987 to 1997. He
served as president of several haematological societies and was Editor of the British Journal of
7 Dr Frederico Duran-Jorda was Clinical Pathologist to the Public Health Department in
Barcelona in 1934. In 1936 he organized a blood transfusion service for the Catalan army using
civilian blood donors. Duran-Jorda F. (1937) El servicio de transfusion de sangre de Barcelona.
Revista de Sanidad de Guerra 1: 307-321.
75 See biographical note 61 above.
Haemophilia: Recent history
Infirmary with Dr Wilkinson, 76 who was Director of the Department of
Clinical Research there, which actually developed from a study of gastric
function into one in pernicious anaemia and is now a department of
haematology. Dr Wilkinson organized the blood transfusion services in the
north-west. He is now over 100 years old 77 and is a vice-president of the
Haemophilia Society. It is fair to say that Dr Duran-Jorda had an original
mind, but I regret to have to tell you that he published one of his original ideas
in Nature in 1947 and it was that red blood cells originate from the granules of
I want to talk a little bit about my early contacts with the use of factor
VIII concentrate, because in 1957, which was when I qualified, Kekwick and
Wolf reported on the use of a factor VIII concentrate in the treatment of six
cases of haemophilia. 79 Two years later I was a Registrar at Lewisham, and
Peter Wolf was still pouring these dreadful soups and thick creamy stuff into
individuals with haemophilia. I was very concerned that they were going to go
into cardiac failure because he was putting in this stuff so fast, but fortunately
they were predominantly young men with good cardiovascular reserves and I
think that apart from a tachycardia and a shortness of breath, we didn't have any
complications. Dr Holman was the haematologist at Lewisham in those days,
and I think it is quite appropriate that we remember that haematologists as we
know them now did not exist. The patients were all under the care of general
physicians and a haematologist was a specialist in the laboratory who got
interested in aspects of blood and blood management. There were very, very
few clinical haematologists.
I went to Manchester in 1965 and that was the year in which Judith Pool
described cryoprecipitate. 81 We didn't get cryoprecipitate in Manchester until
much, much later. We used fresh, so-called 'snap-frozen' plasma. Dr Stratton
was the Director of the Blood Transfusion Service in Manchester at the time
and he was a very autocratic individual. He really believed that all people
wanted from a blood transfusion service was what he called 'the pint', and he
would hold up a bottle of blood, because the blood came in bottles with a
76 Dr John Wilkinson (1897-1998) was Director of the Department of Haematology at
Manchester Royal Infirmary from 1947 to 1962 and set up the first blood transfusion service in
Manchester. He was cofounder of the British Society of Haematology, President of the
European Haematology Society and a Life Councillor of the International Haematology
77 Dr Wilkinson died shortly after the meeting, on 13 August 1998. See biographical note 76.
78 Duran-Jorda F. (1947) Secretion of red blood corpuscles. Nature 159: 293-294.
79 See Kekwick R A, Wolf P. (1957) op. cit. note 22 above.
80 At that time the concentrates came in bottles as an opaque thick creamy juice.
81 See note 24 above.
Haemophilia: Recent history
waist in those days, and he'd say, 'Look at that, doc, that's the pint, that's what
you want'. And all the doctors in the Transfusion Service were called 'Doc' by
the workers, and by Fred [Stratton] himself. He provided a very good service,
but he never thought it was a business of his department to provide blood
So very shortly after arriving in Manchester when I had a baby with a
cerebral haemorrhage, I couldn't get anything other than plasma to treat him
with. In fact I managed to get some cryoprecipitate which was being made for
the first time in Manchester by Dr Watson-Williams at Manchester Royal
Infirmary. It seemed to work, the child recovered, but subsequently died, but it
inspired us to buy a large vacuum flask and we made our own cryoprecipitate.
But whereas in London there had been no difficulty in obtaining blood donors,
because there was a Red Cross panel, you phoned up the Red Cross and they sent
somebody along, any hour of the day or night, Manchester had never developed
that concept. There were special donors, but they all had individual and
particular blood groups and they were called up when a funny blood group was
needed, not when you wanted blood in a hurry. So we had extreme difficulty in
getting donors to provide us with blood from which you could make the
cryoprecipitates. I remember we had to buy the blood bags and we got them
from Tuta (Australia), because they were cheaper than from Baxter, 82 and that
caused problems because the hospital hadn't had to buy blood bags before and
they wouldn't authorize the purchase because they thought that was the job of the
Blood Transfusion Service and, of course, as I told you, the Blood Transfusion
Service wouldn't do it. Eventually we got cryoprecipitate from the Blood
Transfusion Service and continued to use it for a very long time, because there
were no funds to buy imported concentrate.
Actually, this proved to be a benefit, because as a result only a rather small
percentage of our boys developed human immunodeficiency virus (HIV),
because they had been treated with British cryoprecipitate, rather than imported
[contaminated] American concentrate. When cryoprecipitate did become
available Dr Stratton wouldn't provide it to outlying hospitals, and he insisted
that the patients be referred either to me at Manchester if they were children, or
adults to the MRI (Manchester Royal Infirmary) . That led to our setting up our
own Centre in the children's hospital in 1972. That's a little bit about my
What I want to do now is to run through a sort of annual summary of the
way things developed. In the 1970s we were starting to use much more freeze-
dried concentrate in the UK and gradually amounts were beginning to become
82 Manufacturers Tuta (Australia) and Baxter (UK) supplied plastic blood bags to the English
National Blood Authority and Scottish National Blood Transfusion Service.
Haemophilia: Recent history
available. The Bethesda assay for inhibitors was developed in 1975 which
helped standardize assays round the world. 83 Lots of the methods, I think, were
very good, but they weren't used everywhere and, I think, standardization, as we
have just mentioned, was very important. I think the Bethesda assay was helpful
In 1976 the Department of Health published HC-76/4, recommending
three-tier arrangements for haemophilia care. By that time a large number of
hospital laboratories were able to do factor VIII assays and a lot of
haematologists were being appointed because the College of Pathologists was
well under way by then and the concept of having a small centre came into
being. I think it was a mistake, because the Haemophilia Society and those
people who deal with a large number of patients feel that it is better to
concentrate patients in a larger unit where there can be a depth of expertise
rather than in a small unit. The problem with the small unit has always been you
have an enthusiastic haematologist leading it, but when he goes on holiday there
is nobody to take his place and the surgeons don't know anything about it and
the system falls down. That's just a personal view.
In 1978 fetal blood sampling in utero [in the second trimester] enabled us
to check the sex and the factor VIII or IX level, and to offer termination of
pregnancy to those women who wanted it. 85 My experience was that only a
minority of women wanted termination.
In 1982 the gene for factor IX was cloned. Factor IX was cloned before
factor VIII because it is a smaller molecule, not so complicated and was easier
to work on. In the same year, eight individuals with haemophilia and acquired
83 A meeting was held in November 1974, sponsored by the Division of Blood Diseases and
Resources, National Heart and Lung Institute, USA, to address the problem of non-uniform
inhibitor measurement. It was agreed to standardize inhibitor measurements and to describe a
'Bethesda unit' to be used in the measurement of inhibitors arising in haemophiliacs.
See Kasper C K, Aledort M, Aronson D, Counts R B, Edson J R, Fratantoni J C, Green D,
Hampton J, Hilgartner M, Lazerson J, Levine P, McMillan C, Pool J G, Shapiro S, Shulman
N R, van Eys J. (1975) A more uniform measurement of factor VIII inhibitors. Thrombosis et
Diathesis Haemorrhagica 34: 869-872.
84 Department of Health. (1976) Arrangements for the Care of Persons Suffering from
Haemophilia and Related Conditions. HC-76/4. London: HMSO. The three-tier system
comprised Reference Centres (which later became Regional Centres), Haemophilia Centres
and Associate Haemophilia Centres.
83 Rodeck C H, Campbell S. (1978) Sampling pure fetal blood by fetoscopy: in second
trimester of pregnancy. British Medical journal ii: 728-730. Mibashan R S, Rodeck C H,
Thumpston J K, Edwards RJ, Singer J D, White J M, Campbell S. (1979) Plasma assay of fetal
factors VIIIc and IX for prenatal diagnosis of haemophilia. Lanceti: 1309-1311.
86 Choo KH, Gould KG, Rees D J H, Brownlee G G. (1982) Molecular cloning of the gene
for human anti-haemophilic factor IX. Nature 299: 178-180.
Haemophilia: Recent history
immunodeficiency syndrome (AIDS) were reported in the United States. 87 In
1983 parvovirus was found to be spread by concentrates. 88 Factor Vila - that's
plasma-derived factor Vila - was first used in 1983 to treat inhibitor patients
and the first two British cases of haemophilia and AIDS were reported. 89 In
1984 the gene for factor VIII was cloned. I think the initial hope was that
because we could clone factor VIII, we would be able to make an instant
diagnosis, but because it's such a large and complicated molecule there were an
enormous number of defects, and hopes that antenatal diagnosis based on
genetic testing with both factor VIII and factor IX would be easy, proved to be
quite the reverse.
In 1985 tests for HIV were introduced to the Blood Transfusion Service
and in fact tests for HIV became generally available. We were all asked by the
parents of the children we were looking after, 'Please test our children' and
that's what we did. But we read the message wrongly. What they were asking us,
without saying so, was, 'Please find my boy is negative'. In those days when the
first test came out, the concept of counselling was really not very well
understood, and certainly we didn't understand it. We told the parents the
results and then an enormous flood of anxieties and queries came in and people
came and talked to us. It was a topic of enormous interest to patients at the
time. The north-west group of the Haemophilia Society had its annual general
meeting in Manchester. Peter Jones was invited to come and give a talk about
HIV, and 400 people came to
hear him. We had to move into a larger lecture theatre. It was a larger number
than any attendance at a general meeting of the whole Haemophilia Society
But we did have a lot of problems with HIV, not so much dealing with the
individual cases of treatment, but in dealing with children through their parents.
When the test was first introduced, a large number of our boys were quite small,
but as time went by, little boys of 12 became big boys of 16 or 17 and it
became time for them to know. In a children's hospital, it is very difficult to
inquire into the sexual habits of your patients. It is just not in the ethos of a
children's hospital, and we thought that all these boys should know their HIV
status. Whether or not they would actually modify their behaviour we very much
doubted, although we did have condoms available in the Haemophilia Centre. I
87 Evatt B L, Gomperts E D, McDougal J S, Ramsey R B. (1985) Co-incidental appearance of
LAV/HTLV-III antibodies in haemophiliacs and the onset of the AIDS epidemic. New
England Journal of Medicine 312: 483-486.
88 Mortimer P P, Luban N L C, Kelleher J F, Cohen B J. (1983) Transmission of serum
parvovirus-like virus by clotting factor concentrates. Lancet u: 482-484.
89 lones P. (1983) Acquired immunodeficiency syndrome, hepatitis and haemophilia. British
Medical Journal!?,!: 1737-1738.
Haemophilia: Recent history
should not think that many children's hospitals in this country would have
condoms available. It proved very difficult to get them to talk and it proved
impossible to persuade their parents to tell them. Eventually we came to an
agreement that if the boys asked, we would tell them. Various ways and means
were found to raise the topic so the boys actually asked us, so they could be
told. One father came to my office at eight o'clock in the morning and he said,
'I hear what you are planning to do. On no account should my son be told, it
will destroy him'. Eventually the boy found out and said he was grateful to be
told because it was all hushed up so much at home that he thought something
much more serious must be afoot. You will all remember how dreadful it was
at the time with the television advertisements showing rolling waves and
talking about HIV and safe sex, and so forth. 90 When this happened in a
haemophilia household the television was turned off. People just could not bear
up to it, they had to turn their heads away. So our problem with HIV was really
as much dealing with the parents as actually treating the boys who were positive.
Back to the sort of sequence of events. In 1988 recombinant factor Vila was
introduced for treating inhibitor patients 91 and that year was also the first time
that the recombinant factor VIII concentrate was used. 1989 was another
milestone year - hepatitis C was identified. 92 In 1990 the Macfarlane Trust
was set up to distribute funds to people with haemophilia and HIV. In 1992 a
setback came when people realized that solvent-detergent-treated concentrates
could spread virus infections in the form of hepatitis A. 93 By 1993 the Health
Services Guidelines (93/30) came with the recommendation of a two-tier
system of Haemophilia Centres.' They recommended what services should be
available, but made no recommendations whatsoever about what physical
facilities, what buildings, clinics and so forth should be made available, and
that I think has led to certain problems for some Centres. In 1994 the
90 In the 1980s bold television advertisements were used for public education on AIDS. See
Berridge V. (1996) AIDS in the UK. The Making of Policy, 1981-1994. New York: Oxford
University Press, 1 13—1 14.
91 Hedner U, Glazer S, Pingel K, Alberts K A, Blomback M, Schulman S, Johnsson H. (1988)
Successful use of recombinant factor Vila in a patient with severe haemophilia A during
synovectomy. Lancet ii: 1193.
92 Choo QL, Kuo G, Weiner AJ, Overby L R, Bradley D W, Houghton M. (1989) Isolation of a
cDNA clone from a blood-borne non-A non-B viral hepatitis genome. Science 244: 359-362.
93 Mannucci P M, Gdovin S, Gringeri A, Colombo M, Mele A, Schinaia N, Ciavarella N,
Emerson S U, Purcell R H. (1994) Transmission of hepatitis A to patients with hemophilia by
factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. Annals
of Internal Medicine 120: 1-7.
9 This replaced the three-tier system HC-76/4, see note 84 above. Department of Health.
(1993) The Provision of Haemophilia Treatment and Care. Health Services Guidelines HSG
(93)30. London: HMSO. The two-tier system comprised Comprehensive Care Centres and
Haemophilia: Recent history
UKHCDO [United Kingdom Haemophilia Centre Directors Organization] 95
was set up and registered as a charity and by 1997 things were working very
nicely until Creutzfeldt-Jakob disease (CJD) raised its head and produced a
lot of anxiety, not so much for haemophilia but for blood transfusion services in
Other things which have come up, related to haemophilia and which I have
not actually dated, are the use of a continuous infusion of a concentrate. What
has been extremely important, but often ignored, is the introduction of small
needles and butterfly needles and later, in-dwelling venous catheters and Port-a-
Caths for the management of haemophilia care; 97 and another topic which is
covered very little in the UK is radiosynovectomy 98 which has been perhaps
more popular in parts of the world where concentrate has been less readily
Dr Helen Dodsworth: 99 1 used to work at St Mary's Hospital, London, after
working in Manchester, alongside Dr David Evans. May I say briefly
something about the availability of factor VIII concentrate? Although the
manufacturing process was discovered in the early 1950s, 101 there was never
adequate provision for manufacture of factor VIII concentrate in this country
95 See also Rizza's contribution on page 53 below.
96 Giving concentrate by continuous infusion was first reported in 1970. See McMillan C W,
Webster WP, Roberts H R, Blythe W B. (1970) Continuous infusion of factor VIII in classic
haemophilia. British Journal of Haematology 18: 659-667. Bona R D, Weinstein R A, Weisman
S J, Bartolomeo A, Rickles F R. (1989) The use of continuous infusion of factor concentrates in
the treatment of hemophilia. American Journal of Hematology 32: 8-13.
97 Dr Jones remembers how, when he worked as a junior doctor with Dr William Walker (later
first Professor of Haematology in the University of Newcastle upon Tyne), he had to make the
devices that later emerged as butterfly needles and intracaths. Hypodermic needles were cut off
their hubs with pliers and either threaded by, or attached to, thin plastic tubing. The results
were used in the treatment of babies with haemolytic disease of the newborn. Letter to Dr
Daphne Christie, 1 July 1999.
18 See Pietrogrande V, Dioguaardi N, Mannucci P M. (1972) Short-term evaluation of
synovectomy in haemophilia. British Medical Journal!: 378—381. Kay L, Stainsby D, Buzzard B,
Fearns M, Hamilton P J, Owen P, Jones P. (1981) The role of synovectomy in the management
of recurrent haemarthroses in haemophilia. British Journal of Haematology 49: 53-60.
99 Dr Helen Dodsworth FRCP FRCPath (b. 1938) was Honorary Consultant Physician at St
Mary's Hospital Medical School, London, from 1970 to 1993 and Founder Member of the
British Blood Transfusion Society in 1983. She was a Member of the British Society of
Haematology from 1972 to 1993 and has published several papers on blood transfusion-related
topics including: Dodsworth H. (1996) Blood transfusion services in the UK. Journal of the
Royal College of Physicians of London 30: 457-464. Gunson H H, Dodsworth H. (1996) 50 years
of blood transfusion. Transfusion Medicine 6: 1-88.
100 See biographical note 71 above.
101 op. cit. note 23 above.
Haemophilia: Recent history
until the early 1970s. 102 In 1972-73, a unit dedicated to the production of
plasma fractions and managed by the MRC was built on the Elstree site. 103 At
about this time the anticoagulant into which donor blood is taken was changed
from acid-citrate-dextrose (ACD) to citrate-phosphate-dextrose with adenine
(CPD-Ad). ACD has a pH of 5.0 rising to 6.8 after the addition of blood.
Factor VIII, however, is stable over only the narrow pH range of 7.1-7.2, the
final pH achieved when blood is added to CPD. Although the introduction of
CPD-Ad increased the potential for factor VIII production, facilities at
Elstree were inadequate to produce the quantities which were needed.
In 1 976 Pat Mollison, for whom I was working at the time, asked me to
represent him on a committee convened to advise the Department of Health on
how much factor VIII concentrate and albumen were needed to treat patients in
the UK. Our spokesman, Dr Tovey, 105 the Director of the Bristol Transfusion
Centre, had been through a similar exercise for the World Health Organization
in Geneva. He persuaded us that if we wanted to treat our patients adequately, i t
would be necessary to fractionate at least 80 per cent of the blood that was
donated. At this point the Government decided that money was available for
neither extending the fractionation unit at Elstree nor for equipping the
transfusion centres to separate yet more plasma from donor units. So this is
really why we found ourselves buying large quantities of factor VIII concentrate
from America, and why we infected so many of our patients with HIV.
Professor Robert Duthie: 106 I was interested in what Dr Evans has said
about a small unit in a big department. This tends to lead to difficulty in the
admission of haemophilic patients, and the follow-up organization, as well as
educating members of the team. Oxford has been unique, in that haemophilia
102 Anon. (1974) Factor VIII concentrates made in the United Kingdom and treatment of
haemophilia based on studies made during 1969-72. Report of the Medical Research Council's
Blood Transfusion Research Committee Working Party on the cryoprecipitate method of
preparing AHF concentrates. British Journal of Haematology 27 ': 391-405.
103 op. cit. note 62 above.
104 Professor Patrick Mollison FRCP FRCOG FRCPath FRS (b. 1914) has been Honorary
Consulting Immunohaematologist to the South East Regional Service since 1983 and Professor
Emeritus of Haematology, St Mary's Hospital, London, since 1979. He was Director of the
MRC Experimental Haematology Unit from 1960 to 1979 and Consultant Haematologist at
St Mary's Hospital, London, from 1960 to 1979.
105 Dr Geoffrey Tovey FRCP FRCPath (b. 1916) was Director of the South West Regional
Blood Transfusion Centre from 1946 to 1978 and President of the International Society of
Blood Transfusion from 1973 to 1976. He was also Consultant Adviser on Blood Transfusion
at the Department of Health and Social Security from 1979 to 1981.
106 Professor Robert Duthie CBE FRCS (b. 1925) was Professor and Orthopaedic Surgeon in
charge of orthopaedic surgery at the University of Rochester Medical Center, Rochester, New
York, from 1958 to 1966 and Nuffield Professor of Orthopaedic Surgery, University of
Oxford, and Nuffield Orthopaedic Centre, from 1966 to 1992, Professor Emeritus since 1992.
Haemophilia: Recent history
has always been a separate and large department run as a multidisciplinary
specialty with good staffing in all disciplines, e.g. nurses, doctors, teachers,
social workers, physiotherapists, etc. and in the supply of orthopaedic beds for
those haemophiliacs who have musculo-skeletal bleeds, i.e. 85 per cent. I am
afraid that this may be an old argument but I think that one of the real advances
made in Oxford was when the Haemophilic Unit consisted of a full team,
including your sic 'uneducated surgeons' who, with further training can provide a
learning experience for others. HIV, with its biological problems, introduced
an ethical one. Professional people were very much concerned about their degree
of risk and the infectivity of materials from operations. Indeed, in America,
surgeons used this as a new indication for doing or not doing surgery. Because of
the additional risk of HIV, pathologists were refusing to do post mortems or
handle operative material. This ended a very fruitful number of years in which a
much more accurate definition of the local pathology of haemophilia had been
worked out. People were scared of using local tissues for analysis, e.g. by
spectroscopy, and so this form of research ceased. So, HIV had a much greater
impact than just on immunology or infectivity. For example, although HIV
was one of the indications for using synoviorthrosis, this was limited because of
the discovery of chromosomal breakages identified in the patients undergoing
radiosynovectomy. Obviously, in many places in the world where factor VIII
is scarce this is a preferred method, but in England we continue to undertake
surgical synovectomy because of the availability of factor VIII and because of
the knowledge of outcome. 107
One of the reasons why I returned to England from the United States was
the privilege of being able to work in the Oxford Haemophilic Unit, after
having set up a small Orthopaedic Centre in the University of Rochester, New
York. Oxford has provided a large grouping of patients of all ages without the
artificial division of being a child one day and an adult the next. Obviously
haemophilic patients were living much longer, well into adulthood and old age,
with the development of degenerative processes requiring to be operated upon.
This was common until HIV appeared. Suddenly we lost between one-third
and two-thirds of our haemophilic patient population. Indeed, there are now
107 Professor Robert Duthie wrote: 'We discovered that only 10 per cent of haemophilic
patients with chronic synovitis required surgery; the remainder responding to conservative
management by factor replacement, compression bandaging and subsequent careful
physiotherapy. The complications of ongoing haemorrhaging into the musculo-skeletal tissues
were controlled and dealt with in our Centre by conservative treatment. This then allowed
further development in elective orthopaedic surgery: management of severely damaged joints by
replacement; the management of progressive haemophilic cyst formation, by internal fixation
systems in order to prevent pathological fractures, with the increased mortality rates; the
prevention of fixed flexion contractures, caused by muscle haemorrhages, by dynamic splinting,
etc. All giving marked improvement in the musculo-skeletal tissues of mobility, reduction in
deformities and improved function.' Letter to Dr Daphne Christie, 24 July 1998.
Haemophilia: Recent history
two main areas in the epidemiology of haemophilia, pre- and post-HIV
infection. This is of particular importance when it became necessary to examine
our surgical and conservative treatment modalities. A lot of epidemiological
studies have yet to be carried out on the effect of surgery upon the immunology
status of HIV patients.
Lee: Can you talk a little about when you first started doing elective surgery in
these patients and what it really involved for you as a surgeon, and the team
work involved? Can you remember the first elective surgery that you did on
Duthie: Very, very clearly. Charles [Rizza] is smiling as well, because, of
course, the usual discussion which we carried out was about the availability of
factor material, the actual quantity required for the operation, for healing to
take place, and whether or not there was enough. The golden rule was that there
had to be enough on the shelves before we embarked upon any surgery. Then one
changed the surgical attack because of the availability of sufficient factors, and
also because we began to understand the pathology and subsequent healing of
haemophilic tissues which were, and are, different. However, what we had learnt
from poliomyelitis patients all added to the knowledge required to
rehabilitate a haemophiliac after surgery. 108 The simpler the operative
technique the better, because the healing of the tissues would be less demanding
upon factor supply. The development of the factor VIII antibodies was very
critical because with antibodies elective surgery was contraindicated. Actual
operating techniques were modified by use of electrocautery, compression post-
operatively, and fibrin injection into haemophilic cysts and their walls. We
devised a type of sterile air operative enclosure in Oxford in order to reduce,
to the lowest level possible, surgical infection rates in the haemophilic patient,
with great success. It became even more important when we were operating on
HIV patients (up to two a week), in being able to isolate and reduce the
surgical team with more control
108 Professor Robert Duthie wrote: 'This aspect of rehabilitation is highly specialized and
carried out by many committed individuals, e.g., nurses, physio-occupational therapists and
social workers. The aim is to restore the patient back to school or to work, by overcoming
muscle weakness, stiffness and joint immobility, negative attitudes towards educational, daily
living and recreational activities. Working under haemostatic control by factor replacement,
dynamic splintage, orthotics, compression air splints, new skills of proprioceptive
neuromuscular facilitation (TENS - transcutaneous electrical nerve stimulation) are now
available to improve the results of surgery and the treatments of bleeds.' Letter to Dr Daphne
Christie, 22 March 1999.
Haemophilia: Recent history
in the numbers around the patient, handling the patient, materials
and instruments. 109
Lee: Dr Matthews, could I try and encourage you to talk a bit about the
beginnings of treatment for patients, regular home treatment for patients, and
maybe we can draw out of you a bit about needles and the changes that came in
with decent needles and things like that.
Dr James Matthews: 110 I came to Oxford in 1961 and before that time
transfusion equipment was rather unreliable. The rubber and glass drip sets
sometimes came apart in the middle of a transfusion and created havoc.
Needles and syringes in 1961 were still of a type that had been used for many
decades. Needles were all steel, sterilized by autoclaving after use and
resharpened in a machine similar to that used for sharpening gramophone
needles. They were sometimes blunt or even had a hooked point! They were
packed for use in glass tubes and the size was identified by a twist of coloured
cellophane which closed off the end of the tube. The syringes were of glass and
sometimes stuck whilst drawing blood or giving an injection, usually at the
worst possible time, particularly if you were dealing with a child. For some
time after I came
syringes were autoclaved in aluminium canisters. Blood sample tubes for
coagulation studies were prepared in the laboratory, as were pipettes and many
of the test reagents.
When dealing with bleeding patients in the early days, one of the main
problems was shortage of treatment material. The material most commonly
used was fresh-frozen plasma. This was a material which was relatively easy to
obtain and became more plentiful as the blood transfusion organizers allocated
more for the treatment of haemophilia. We were very fortunate in Oxford in
having Dr Jean Grant as Director of the Blood Transfusion Service. She was one
of many consultants who cooperated closely with the Haemophilia Centre. 1 1
was a time when the clinicians at the Haemophilia Centre had access to the key
of the Blood Transfusion Centre and could obtain plasma out of hours without
delay. Plasma was used for the treatment of many of the common bleeding
109 Professor Robert Duthie wrote: 'Because of having sufficient numbers going through our
specialized operating facilities the discipline and the efficiency of the team were readily
worked out, and indeed there was no further need to use HIV as an excuse or as another indicator
of whether surgery was indicated.' Letter to Dr Daphne Christie, 24 July 1998.
110 Dr James Matthews (b. 1930) was Clinical Research Fellow at the MRC Blood Coagulation
Research Unit, Churchill Hospital, Oxford, from 1962 to 1965, with a special interest in the
clinical management of haemophilia and other bleeding disorders. He remained at the Oxford
Haemophilia Centre as an Associate Specialist until his retirement in 1991.
Haemophilia: Recent history
episodes which responded to the limited factor level achievable with the
material. Allergic reactions were not uncommon and the volume of infusion
required was a disadvantage particularly in children who might be upset and
restless at the time. A few years passed, and more of the human and animal
factor VIII concentrates became available and treatment became easier in
terms of the volumes used and the factor levels which could be achieved. Home
treatment was not used for some time as the materials were in short supply and
those which were available were not really suitable for using at home.
Lee: Was it right to think that cryoprecipitate was a thing that really pushed
Matthews: It did make a big difference, because it was easily made. It still
wasn't the ideal material because it was a liquid plasma product stored in the
frozen state but many Centres found it a very useful material for home
Lee: In our own Centre, Katharine Dormandy really made a major
contribution. I think I am right in saying that she made cryoprecipitate in the
old hospital at Lawn Road in the labs there, 112 and that the patients were
actually started on home treatment with cryoprecipitate. In fact, if you go back
and look through the notes of some of our older patients, the social work
contribution was to raise the money to buy the deep freezers enabling them to
have it at home.
Rizza: I think Katharine Dormandy was one of the few to start using cryo
[precipitate] for home therapy. I remember having a discussion with her about
the problems of fridges without alarms on them, because if the patients were
going to keep cryoprecipitate at home, deep frozen, then they had to know if
the fridge had gone off, when they went away for the weekend. They had to have
an alarm system fitted and those were very expensive at that time.
111 Dr Katharine Dormandy FRCP (1926-1978) qualified at the Royal Free Hospital School
of Medicine in 1951 and was appointed Senior Lecturer in Haematology in 1964 and Reader
in Haematology in 1970. She developed the Haemophilia Centre at the Royal Free Hospital,
London, raising money personally and campaigning tirelessly for better treatment for people
with haemophilia and better educational opportunities for haemophilic boys. She was a
pioneer of home treatment. In 1977 she was awarded the first gold medal of the Haemophilia
Society. The Centre named in her honour was opened in 1978. See also notes 114, 125, 170 and
112 See note 171 below.
Haemophilia: Recent history
Lee: There's a sort of interesting twist in that tale, which Ted [Tuddenham]
might throw a bit of light on. In our Centre we were a bit slow to use large full
clotting factor concentrate, because it wasn't really until you and Peter Kernoff
came that people were started on this treatment, because Katharine had been so
taken up with the cryoprecipitate. Is that fair?
Matthews: I think it is probably fair to say that we used the freeze-dried
pooled plasma concentrate in preference, because it was available to us and
seemed a suitable material for home treatment.
Professor Edward (Ted) Tuddenham: 113 Katharine had a wonderful
relationship with her patients. It was maternal in some ways, because she knew
them all very well and their social circumstances, she put a very great deal of
effort into ensuring that they would have the best possible circumstances for
home treatment. She was a pioneer in that area and obtained, as you
mentioned, money for them to have freezers in their own homes in which they
kept cryoprecipitate. I would say that, to be fair to Katharine, it was difficult,
as other speakers have mentioned, to obtain adequate supplies of higher-purity
concentrates other than for surgery, and the Centre's treatment relied very much
on cryoprecipitate produced through local blood transfusion centres. Things
changed, of course, when Peter Kernoff and I came in after Katharine tragically
died, and the concentrates were brought in progressively through battles against
the controllers of the finances. Although to do them justice, they did
progressively increase the fraction of local capital that was being expended on
imported concentrates until they reached towards the dizzying heights of today.
So it was a transitional phase. Katharine was a pioneer and it undoubtedly
changed the lives of our patients at that time to have their own freezers filled
with locally produced cryoprecipitate.
113 Professor Edward Tuddenham FRCP FRCPath (b. 1944) was Co-director of the
Haemophilia Centre, The Royal Free Hospital, London, from 1978 to 1986, and Director of
the MRC Haemostasis Research Group at Northwick Park Clinical Research Centre from
1987 to 1994. He has been Director of the Haemostasis Research Group, Clinical Sciences
Centre, Imperial College Medical School, London, since 1994 and Honorary Consultant
Haematologist at the Hammersmith Hospital, London, since 1994. He is a Member of the
World Federation of Hemophilia, the International Society on Thrombosis and Hemostasis,
and the British Society of Hemostasis and Thrombosis.
114 See for example Le Quesne B, Britten M I, Maragaki C, Dormandy K M. (1974)
Home treatment for patients with haemophilia. Lancet ii: 507-509. Ingram G I, Dykes S R,
Creese A L, Mellor P, Swan A V, Kaufert J K, Rizza C R, Spooner R J, Biggs R (1979) Home
treatment in haemophilia: clinical, social and economic advantages. Clinical and Laboratory
Haematology 1: 13-27.
Haemophilia: Recent history
JoneS: Yes, just to go back to cryo [precipitate]. Judy Pool discovered cryo
[precipitate] 115 - it was another case of serendipity really. She was looking at
the various bits of concentrate and she was going to throw away the gunge. I
think it was Shannon who decided to test the gunge for factor VIII and
discovered all the factor VIII was in the gunge and that was cryoprecipitate.
Judy came to Newcastle in the mid-1960s and the day after her visit the blood
transfusion service made the first pack of cryoprecipitate. The introduction of
cryo [precipitate] revolutionized the care of children, because previously we had
to give so much fresh-frozen plasma, particularly to patients with factor IX
deficiency because of their poor response, that they used to go into heart failure.
So they were all on digitalis and diuretics and they lay in bed on the dreaded
drip, and it was hardly surprising that they never wanted to come to hospital
again. But if they bled sufficiently they had to! My first patient was in hospital
27 times before his fifth birthday and, worse than that, he saw 17 different
doctors. Nobody was interested in haemophilia. Haemophilia was 'a bloody
nuisance' and kids with haemophilia were 'bloody nuisances'. Only one in 16
000 of the population has severe transfusion-dependent haemophilia, and so it's
easy to see where the resistance came from. There was great resistance,
particularly from the Blood Transfusion Service of this country and certain of
its directors, to treating haemophilia at all, except as a hospital disease. There
was great resistance to home therapy. There were letters in the medical press
and the lay press, suggesting that people with haemophilia were not capable
of treating themselves, that their parents should not take responsibility for them
at home, that it was dangerous and unethical and immoral to put treatment into
their hands. In two European countries, Italy and, I think, Spain at the time, it
was illegal for patients to inject themselves with any medication, including
factor VIII or factor IX. So there was an enormous inertia to overcome. The
other feature of medicine in those days that we tend to forget was its
paternalistic nature; the doctor always knew best, nurses really didn't come into
it, and it was thought that it was not right to educate patients. It sounds terrible
See note 24 above
116 The difficulties in implementing home therapy because of the shortage of concentrates are
reported in the Lancet in 1974. See for example Biggs R. (1974) Supply of blood-clotting
factor VIII for treatment of haemophilia. Lancet v. 1339. Lay articles about the shortage and the
difficulties for both patients and staff, including comments opposing home therapy, were
published in the Yorkshire Post in 1975 and 1978. Dr Jones was Chairman of the UK Home
Therapy Working Party at the time, and reported the situation in the UK in the British Medical
Journal. See Jones P, Fearns M, Forbes C, Stuart J. (1978) Haemophilia A home therapy in the
United Kingdom 1975-1976. British Medical Journal i: 1447-1450. Mr Clifford Welch's
recollections of home treatment for haemophiliacs at that time are written in a letter to
Dr Daphne Christie, 5 July 1999, and will be deposited with the records of this meeting in the
Contemporary Medical Archives Centre of the library of the Wellcome Institute for the
Haemophilia: Recent history
to say that now, but we are talking about 30 years ago. It was for the doctor to
say when patients needed treatment. That's one of the reasons the children of
that generation grew up crippled with haemophilic arthritis. 117
There wasn't enough plasma being collected. When cryo [precipitate] came
in there was just enough to be able to perform outpatient treatment, there wasn't
enough for home therapy. There wasn't enough plasma going through to the new
Elstree site to make concentrate and that was one of the reasons why the
Government decided to bring in concentrate, particularly from the United
States of America. This decision should be seen against the background of a
very, very rare disorder in the multitude of medical conditions, and the
resistance that there was to the treatment which had been developed in Oxford,
and to allowing patients to start treating themselves.
Mrs Riva Miller: 118 I am from the Royal Free and I very much appreciated
Dr Evans's talk, because it certainly reminded me that in 1958 I was at the
Manchester Royal Infirmary and worked on the Leukaemia Unit, so I had some
connections back there. Let us come back to Dr Dormandy and home treatment.
She employed me in 1966 to look into the home circumstances of all the
patients, particularly the children and how much they missed school, to see
whether we could start to think about home treatment. That was an enormous
survey which really had quite an impact. 119 It was Dr Tuddenham's foresight
and persistence that secured a position to look into all the other needs of
people, that helped me to stay there until today, although that position is being
EvanS: I want to contradict Peter Jones, because I worked in a children's
hospital and I think actually it's very different in children's hospitals. At the
time we were introducing home treatment, we were positively encouraged by
117 Dr Peter Jones wrote: 'There was no treatment at home and the parents were usually very
reluctant to take them to hospital'. Letter to Dr Daphne Christie, 5 July 1999.
118 Riva Miller (b. 1935) is a social worker and a trained family therapist with particular
interests in HIV/hepatitis and close involvement in orthopaedic clinics, and has worked in the
Royal Free Hospital Haemophilia Centre since 1966. Her main interest has been in
integrating the social, psychological and medical aspects of the lives of people with
haemophilia and their families into the day-to-day work of the Centre, particularly in busy
clinics. She currently runs the AIDS Counselling Unit at the Royal Free NHS Trust and has a
consultancy at the Blood Service in North London. She has worked for the World Health
Organization running workshops for haemophilia and AIDS.
119 Rizza C, Spooner R J D. (1977) Home treatment of haemophilia and Christmas disease: five
years' experience. British Journal of Haematology 37: 53-66. idem (1983) Treatment of
haemophilia and related disorders in Britain and Northern Ireland during 1976-80; report on
behalf of the directors of haemophilia centres in the United Kingdom. British Medical Journal
Haemophilia: Recent history
everyone to do so. We were appointing nurses to look after children with cystic
fibrosis at home, nurses to look after children with diabetes at home, and as
soon as I wanted to introduce a home treatment programme I was encouraged
to do so and I was provided with a nursing sister to help do it. I think that was
the difference between adult centres and the children's hospitals, which were
quite independent. The second thing, of course, about cryoprecipitate for home
treatment is that little children only need little doses, so it was much easier for
the parents to be trusted to draw up a few bags of cryoprecipitate rather than the
enormous number of bags that you have to do for an adult.
Colvin: I wanted to say a couple of words in support of what Riva [Miller]
was saying, and to mention Katharine Dormandy's influence on trying to
provide comprehensive care for all the children, and indeed, adults, in the
North-East Thames region. "When Professor Jenkins 120 was Director of the
London Hospital Haemophilia Centre, he and Katharine got together in the
early 1970s and organized a haemophilia nurse to go round the whole of our
huge region, seeking out people with haemophilia and that was really the
beginning for us of the idea of having a home treatment programme on a large
basis. I think it is important to know that Katharine, just before she died, made
a really big impact on finding out just exactly who'd got haemophilia in our
region and set up the possibility of treating them all, instead of just some of
Lee: In my room in the hospital I found a book which has got the minutes of
those meetings and what is so amazing is that there is an account of the number
of bottles of concentrate that were being issued in the region: they are minuscule
amounts. One of the things that Charlie [Rizza] was talking about the other day,
was that you got as many bottles as your local transfusion centre provided the
Rizza: Yes, there was a time when the factor VIII produced by Elstree was
delivered pro rata to the different Haemophilia Centres, so that if a region put
in large amounts of plasma centrally to be fractionated, it got large amounts of
factor VIII back to the Haemophilia Centre. If the region put in only a small
amount of plasma to be fractionated centrally, then that region got a very small
amount of factor VIII. That made difficulties for some large centres which had
Blood Transfusion Centres which were not giving large amounts of plasma
120 Professor George Jenkins FRCP FRCPath (b. 1927) was Consultant Haematologist at
the Royal London Hospital from 1965 to 1992 and President of the British Society of
Haematology in 1988.
Haemophilia: Recent history
through central organizations for fractionation. I think that system has now
fallen into disrepute.
Lee: We have heard so far this afternoon only from the people who were giving
out the care. We haven't really heard much of the history of things from the
people who were receiving the care. I wonder if I could encourage some
comments about that?
Reverend Alan Tanner: 121 I am very interested in the saying of Gwyn
Macfarlane, 'One has to remember what it was like not to know things which
now seem self-evident', because, I think, testifying from the point of view of a
father of a patient, it is worth remembering the change in attitude and lifestyle
which took place at these various stages. I was very interested to hear the
mention of 'comprehensive care', which was one of the major advances in
treatment, care management and so on. But going right back to the beginning,
some have heard me testify before about my introduction to haemophilia with
Professor Hardisty, because my own son was diagnosed at Great Ormond
Street. Then, as I have said many times, there was no treatment except Russell's
viper venom. 123 Russell and the viper have been much maligned in the past, but
were of great comfort in moments of crisis.
Lee: We are talking about 40 years ago, aren't we?
Tanner: Yes I am going right back - 40 years. The facilities provided were
minimal. Russell's viper venom for crises, plasma, a pat on the back, tender
loving care and all that. So we need to remember the transformation which
came with the introduction of cryoprecipitate. I am a Royal Free Hospital
supporter, so I can speak again about Dr Katharine Dormandy. One of the things
we haven't mentioned yet is that Dr Dormandy introduced boys to treating
themselves at a very, very early age. When parents thought they were taking over
the management of injecting cryoprecipitates, Dr Dormandy was very firm: the
boys were going to exercise that sturdy independence, and begin to treat
121 The Reverend Prebendary Alan Tanner (b. 1925) was Chairman of the Haemophilia Society
from 1976 to 1997, Chairman of the World Federation of Hemophilia from 1973 to 1995 and
Chairman of the Macfarlane Trust since its foundation in 1988. He has three daughters and
one son who was diagnosed with haemophilia at the age of five in I960 and died in
October 1998, as a result of HIV infection and hepatitis C virus (HCV) through the use of
contaminated blood products.
122 See biographical note 73 above.
123 op. cit. note 19 above.
Haemophilia: Recent history
themselves and that was when they began, as it were, to wean themselves from
centres, doctors, and all that. So that's cryo [precipitate] for a start.
It was round about that time that we obviously looked to Oxford for the
kind of academic support in these endeavours, and at the same time I have to
pay tribute to Professor Ingram who was my mentor in those days. I often
remember he was the one whom I asked, 'How do you say amniocentesis?' He
told me and explained what it meant, and that was another part of my tutoring
in the whole endeavour. And then, as we have mentioned, with the introduction
of concentrates, that was where comprehensive care came in. Dr Jones won't
mind my mentioning the transformation that took place at his centre when he
took over Newcastle. He was one of the first to introduce comprehensive care
with a team which included an orthopaedic surgeon, a dental surgeon,
physiotherapists, social workers and so on. He developed what we used to call
the 'heavy gang' in Newcastle, which, I think, he took on tour to show how it
could be done. So then again, it's a transformation taking place, not only in a
physical sense, but in that development of independence, and in emotional
maturity, because for the boys and men, when they were introduced to these new
concepts of treatment and management, their lives were transformed. Where
they had previously been tied to a centre, they then began to travel. I speak from
experience of those who came to the World Federation of Hemophilia; 124 they
were released, made free, and there was a tremendous sense of liberation.
We then go onto the other stages with the introduction of HIV infection
and hepatitis, and now possibly CJD. That's a sad part of the drama, but up to
that stage there was that very, very significant transformation of life. I could
speak forever about that, but I think that's probably enough to emphasize the
Mr Clifford Welch: 125 I was born in 1925 and haemophilia was diagnosed
when I was a year old by my falling out of my highchair and tearing the
fraenum in my upper lip. Thereafter, very fortunately, I had a perfectly normal
life, having only mild haemophilia, so I enjoyed my school days, but life at
home was really severely shook up when, at the age of five, my mother
produced triplets who also had haemophilia and it was that which brought us
into contact with Professor Macfarlane, Dr Macfarlane as he then was, at Bart's.
It was in 1934 when one of my brothers was admitted to Bart's with a severe
124 For an account of the history of Haemophilia Societies and the World Federation of
Hemophilia, see note 5 above, 12-13 and note 169.
12 Mr Clifford Welch CBE FIM (b. 1925) trained as a materials engineer. He also pursued a
career in scientific and technical publishing, and served on the Design Council from 1993 to
1998, latterly as Chairman. He has been associated with the Katharine Dormandy Trust for over
20 years and Chairman for the majority of that time.
Haemophilia: Recent history
haemorrhage and, I think, two of them were treated there for long periods. We
also used to go up and see Gwyn Macfarlane regularly every few months while
he took blood tests. After he retired I remember getting a letter from him in
which he said how he watched his delicate apparatus in his small room at Bart's,
most of which was constructed from Meccano, 126 being crawled over by my
three brothers like monkeys, wondering whether it was all going to get torn to
pieces or not. But he was really a wonderful supporter to my mother, because at
that time in the 1930s there really was, as Alan Tanner has said, no treatment
other than the Russell viper venom. I can remember cycling to John Bell and
Croyden in Wigmore Street 127 on a Sunday to get Russell viper venom for one
of my brothers with a serious external bleed. But apart from that the real
miracle was Macfarlane introducing the concept of blood transfusions from my
mother to the boys, which, of course, in the late 1930s saved their lives on a
number of occasions. 128 Then in 1941, or 1942, we came into contact with Frank
Smith 129 who was one of the early members of the Haemophilia Society. He
had a flat off Baker Street and I can remember going to one of the first
meetings of the Society with my mother in an air raid and listening to him
explaining that the only sure treatment was Dr Timperley's egg white 130 and
this was very seriously propagated by him for many years afterwards. It was a
tragedy because despite his deep concern that Dr Timperley's work did not
meet with success, Frank Smith made a major contribution to getting the
Haemophilia Society going. But as far as I was concerned I had a charmed life
really, and the only time I was seriously injured I was cared for in Bart's,
during the war, when Dr Black and Charles Fletcher looked after me with
advice, I gather, from Dr Macfarlane, who by then was
Lee: Last week when we went to interview Dr Rosemary Biggs, 131 I asked,
'What was Macfarlane doing all the time? Was he locked up in the laboratory,
126 Macfarlane devised a number of apparatus, in part made of Meccano. See for example
Robb-Smith A (1993) op. cit. note 3 above, 51. Macfarlane R G, Tomlinson A H. (1961)
An apparatus for measuring the tensile strength of blood clots. Journal of Clinical Pathology
127 John Bell and Croyden was a well-known pharmacy in London.
128 op. cit. note 20 above.
129 Frank Smith was one of Macfarlane's haemophilic patients and main organizer of the
International Haemophilia Society.
130 That is treatment with a bromide extract of egg white. Timperley found that if egg white is
incubated at 37°C with potassium bromide for several days it was possible to extract a substance
which on intravenous or intramuscular injection reduces the clotting time of blood and
controls haemorrhage in haemophiliacs. See Timperley W A, Naish A E, Clark G A (1936) A
new method of treatment in haemophilia. Lancet ii: 1142-1149. See also page 53 below.
131 op. cit. note 2 above.
Haemophilia: Recent history
or did he get involved with the patients at all?'; and Dr Biggs replied, 'No, he
didn't really get into our first patients. There were one or two patients he
remembered from St Bartholomew's Hospital. One I remember was a set of
triplets with haemophilia (that is, Clifford's brothers)'. And then I went on to
explain what has happened to them since and she rounded off the conversation,
'...They weren't angels, they were absolutely all over the place. I know
Professor Macfarlane had them in Bart's when they were three or four and he
said they were absolute menaces about the laboratory'. But it's interesting that
you talk about the Meccano, because I have another patient who remembers
Macfarlane from Bart's and keeps talking about this Meccano that was
presumably shaking the tubes for the tests.
Douglas: Since you returned to Dr Biggs' earlier recollections, it is
appropriate to give my reminiscences of Oxford between 1951 and 1953 at this
stage. My time in Oxford preceded the major later endeavours to treat
haemophilia. I had the enormous privilege of working with Gwyn Macfarlane,
Rosemary Biggs and Ethel Bidwell. This experience shaped my academic
interest in haemostasis and thrombosis after I left Oxford. My initial ignorance
was a shock to Rosemary and Ethel, but after a few months of their training I
was ready to do experiments. In the work which followed my name appears on
several papers; 132 my name is there because I helped to do a lot of experiments
but the ideas for these came from Dr Macfarlane and Rosemary Biggs. I arrived
in Oxford at a time when there was about to be a breakthrough from their
previous experimental work, especially their study of thrombin generation from
I had some earlier interest. In 1944, on my first day as a house physician
after graduation, a teenage haemophiliac had a single tooth extracted and the
socket bled for three weeks after. Three years later a severe haemophiliac, who
had been under my care, died from coronary thrombosis. This taught me that
thrombosis was not entirely due to blood clotting.
I have quoted reminiscences here. I still remember a lot of things
Macfarlane said, such as, 'Reminiscences are only really of interest to those who
are telling them,' but more importantly, and it's already been quoted today,
'One has to remember what it was like not to know things which now seem self-
132 See for example Biggs R, Douglas A S, Macfarlane R G. (1953) The initial stages of
blood coagulation. Journal of Physiology 122: 538-553. Douglas A S, Biggs R. (1953)
Consumption of some components involved in physiological blood coagulation.
Glasgow Medical Journal 3A: 329-342. See also note 17 above.
133 See also Reverend Alan Tanner's recollections on page 39 above.
Haemophilia: Recent history
And in 1951 we did not know much. We knew using Quick's one-stage
prothrombin time test that citrated or oxalated plasma clotted on the addition
of tissue extract and calcium. 1 Some years later Quick noted when oxalated
plasma was left standing on the bench, the clotting time of this plasma in his
test lengthened; he assumed this to be a 'labile factor'. 135 Working in Norway
during the war, Owren described a genetic coagulation defect with a prolonged
one-stage test not due to prothrombin deficiency. 13 This was called factor V
and was the same as Quick's 'labile factor'. We also knew at around that time
that there was another factor involved and that was factor VII. 137 It had been
shown in the late 1940s that normal serum (containing no prothrombin nor
factor V) shortened the one-stage test of coumarin plasma. 138 This led to the
discovery of factor VII.
Up to 1951 coagulationists had been mainly concerned with the action of
tissue which produced rapid coagulation of blood. However, it was known that
blood collected by clean venepuncture without tissue contamination did
coagulate, albeit more slowly. This unknown intrinsic pathway for clotting had
been neglected too long and its time came in Oxford in 1952. Previous studies
had shown that normal blood delivered to a glass tube coagulated in five to ten
minutes and that prothrombin was rapidly consumed. In haemophilia and
thrombocytopenia, prothrombin consumption was defective and the plasma
factor missing in haemophilia (so-called antihaemophilic globulin), and
platelets were likely to be two components of an intrinsic pathway. 139
134 According to the classical theory of coagulation, prothrombin was converted to thrombin
and thrombin clotted fibrinogen (see Appendix). Quick A J. (1935) The prothrombin in
hemophilia and in obstructive jaundice. Journal of Biological Chemistry 109: lxxiii— lxxiv.
Quick A J, Stanley-Brown M, Bancroft F W. (1935) A study of the coagulation defect in
hemophilia and in jaundice. American Journal of the Medical Sciences 190: 501-51 1.
135 Quick A J. (1943) On constitution of prothrombin. American Journal of Physiology
136 Owren P A (1947) Coagulation of blood: investigations on a new clotting factor. Acta
Medica Scandinavica 128: 1-327.
137 de Vries A, Alexander B, Goldstein R. (1949) Factor in serum accelerates conversion of
prothrombin to thrombin: its determination and some physiologic and biochemical
properties. Blood A: 247—258. Roller F, Loeliger A, Duckert F. (1951) Experiments on new
clotting factor (factor VII). Acta Haematologica 6: 1-18.
138 Fahey J L, Olwin J H, Ware A G. (1948) Effect of dicoumarol on Ac-globulin and
prothrombin activity. Proceedings of the Society for Experimental Biology 69: 491-494.
139 Dr Charles Rizza wrote: 'Blood coagulation can proceed by the intrinsic or extrinsic
system, two separate but interlinked routes. In the intrinsic system only the plasma coagulation
factors are involved. In the extrinsic system tissue factor plays an important role (see Appendix).
In haemophilia the intrinsic system is defective because of lack of factor VIII, an essential
component. The fact that haemophilic tissue (brain) when added to haemophilic blood brought
about normal clotting was evidence that haemophilic tissue was normal and that the
haemophilic-clotting defect was due to a failure of the intrinsic system.' Letter to Dr Daphne
Christie, 3 July 1999.
Haemophilia: Recent history
Before I arrived in Oxford I had worked in Glasgow Royal Infirmary,
where the brain from a patient who had died of haemophilia was as powerful as
normal brain in clotting haemophilic plasma. The extrinsic pathway in
Early in 1952 another important patient was studied, and in my way of
thinking was more important than the Christmas factor-deficient patient,
studied five months later. The patient was under the care of Professor L J Witts
in Oxford. He was a 26-year-old man who had an acquired coagulation
defect with bruising epistaxis [nose bleed], gum bleeding and haematuria. He
had a one-stage prothrombin time of 18-22 seconds compared to a normal
plasma result of 14 seconds. When brain was added to his plasma and this then
recalcified, thrombin developed immediately, but it was very little compared
to that from a normal plasma. Rosemary [Biggs] had the foresight to do
critically important experiments on this plasma, and I can still remember her
doing these experiments. She diluted this plasma, recalcified it and then took
aliquots using them in lieu of brain in a one-stage prothrombin time and finding
as powerful thromboplastic activity as brain, developing after four to five
minutes incubation. At the same time she subsampled on to fibrinogen and
found no important amounts of thrombin. On 20 February 1952 she posted a
letter to Nature which records her personal contribution to the enormous
discoveries that were made in that year and launched a whole new era of blood
coagulation research. 141
Two simple plasma fractionation procedures were in use. When alumina
was added to plasma this removed prothrombin and factor VII leaving, after
centrifugation, factor V and antihaemophilic globulin in the supernatant
'adsorbed plasma'. After centrifugation, elution from alumina precipitate
recovered prothrombin and factor VII. A second fractionation method was
ammonium sulphate precipitation producing crude preparations of factors V
and antihaemophilic globulin. Platelets were prepared by differential
centrifugation. Rosemary made a preparation of antihaemophilic globulin from
ammonium sulphate precipitation of adsorbed normal plasma and a factor VII
preparation from adsorption of serum, and when she incubated these three with
calcium a powerful thromboplastin was formed.
140 Professor Leslie J Witts (1898-1982) was Nuffield Professor of Clinical Medicine at
Oxford from 1938 to 1965 and a Fellow of Magdalen College. From 1963 to 1968 he was a
member of the Committee on Safety of Drugs and Chairman of the Subcommittee on Adverse
141 Biggs R. (1952) Plasma thromboplastin. Nature 170: 280.
42 Details of the plasma fractionation procedures are given in Biggs R, Macfarlane R G.
(1953) op. cit. note 37 above, 71 and 343.
Haemophilia: Recent history
Following the findings described in Nature in early 1952, we used diluted
adsorbed normal plasma as a source of antihaemophilic globulin, diluted
normal serum as a source of factor VII and washed platelets with calcium to
make a powerful thromboplastin. This became the work-up of the
thromboplastin generation test.
In June 1952 we submitted a manuscript on the formation of
thromboplastin in human blood to the Journal of Physiology. 1 3 It was published
early in 1953 by which time we knew that the property of serum was not due
solely, if at all, to factor VII.
The early features of the thromboplastin generation test were the
abnormality present in the adsorbed plasma in haemophilia, and the abnormal
behaviour of coumarin serum (initially attributed to factor VII). Also
circulating anticoagulants could be detected, and abnormal platelet function in
Then one day in July 1952, I was asked to apply the thromboplastin
generation test to two haemophiliacs where Merskey's 'plasma mixing
experiments' 1 had shown cross-correction. One of the blood samples came
from John Dacie and Bob Pitney at the Hammersmith Hospital [the patient was
Stephen Christmas] and the second was an Oxford patient previously studied
by John Poole. 145 Their adsorbed plasma behaved normally in the test but their
serum was abnormal.
The test therefore provided a method for telling the two 'haemophilias'
apart and provided immediately a worldwide reference to help differentiate
the two disorders. When seven patients had been collected, from amongst
previous postgraduate students at Oxford, including Clarence Merskey, the
'new' disorder was published in the British Medical Journal in December
1952. One of the families described revealed a sex-linked recessive type of
inheritance, making the two disorders not only clinically but genetically
The thromboplastin generation test became important not only in the
laboratory diagnosis of clinically suspected bleeding disorders, but was
modified to produce assay techniques for antihaemophilic globulin (factor
VIII) and Christmas factor (factor IX), these being essential in the therapeutic
endeavours which developed later. We published two other papers on the
143 Biggs R, Douglas A S, Macfarlane R G. (1953), op. cit. note 17 above.
14 op. cit. notes 35 and 36 above.
1 5 See biographical note 33 above and Sir Christopher Booth's contributions below.
1 s op. cit. note 1 8 above.
Haemophilia: Recent history
intrinsic pathway in the Journal of Physiology. w Factor V as well as factor VIII
in the adsorbed plasma were shown to be needed. Dr Macfarlane often talked
about an amplifier and we did some experiments realizing that all the known
components (factors V, VII, VIII, IX and platelets) were unlikely to react
together simultaneously. Our reagents were too impure to make significant
progress and it was not until
ten years later that Gwyn Macfarlane recognized his amplifier to be an
Sir Christopher Booth: 149 I think I should, as a historian of the
Hammersmith Hospital, inject two of Hammersmith's contributions into this.
The first is that after Gwyn Macfarlane went to work at Hammersmith, from
1935 until the war, he wrote his thesis on disorders of the clotting mechanism
for which he obtained a gold medal of the University of London. 150 I found that
thesis when I was writing my own thesis in the 1950s and I modelled my thesis
on his. I am happy to say that I got a gold medal too. But that isn't what I
wanted to say. The point about the Christmas case was that the original case was
a patient of the late Sir Graham Bull, 151 who attended at Hammersmith with
bleeding of the tongue, this boy having bitten his tongue. And it was that
patient, referred to Professor John Dacie's department, on whom W R Pitney 152
did a thromboplastin generation test 153 which came out wrong, and he couldn't
understand it. So he went down to see John Dacie and it was Dacie, who knew
147 Biggs R, Douglas A S, Macfarlane R G. (1953) op. cit. notes 17 and 132.
148 Macfarlane R G. (1964) An enzyme cascade in the blood clotting mechanism, and its
function as a biochemical amplifier. Nature 202: 498-499. idem (1966) The basis of the
cascade hypothesis of blood coagulation. Thrombosis et Diathesis Haemorrhagica 15: 591-602.
1 9 Sir Christopher Booth Kt FRCP (b. 1924) trained as a gastroenterologist and was Director
of the Clinical Research Centre of the Medical Research Council, from 1978 to 1988. He was
the first Convenor of the Wellcome Trust's History of Twentieth Century Medicine Group,
from 1990 to 1996, and Harveian Librarian at the Royal College of Physicians from 1989 to
150 Macfarlane R G. (1938) The normal haemostatic mechanism and its failure in the
haemorrhagic states. MD thesis, University of London.
151 Sir Graham Bull Kt FRCP (1918-1987) joined the Postgraduate Medical School in
Hammersmith in 1947. He was appointed to a lectureship in the Department of Medicine and
later was in charge of the renal unit where he developed a treatment that became renowned for
its use in the acute phase of renal failure. He served as a member of the Medical Research
Council from 1962 to 1966 and was appointed director of the Medical Research Council's
Clinical Research Centre at Northwick Park in 1966. He was second Vice-President of the
Royal College of Physicians from 1978 to 1979.
152 Professor W R Pitney ('Bob' mentioned on page 45) (1921-1986) carried out research into
blood disorders at the Royal Postgraduate Medical School in Hammersmith, London, and was
Dean of the Faculty of Medicine at the University of New South Wales from 1984 to 1986, and
President of the 21st International Congress of Haematology in 1986. Much of his research
work focused on coagulation factors (see also notes 18 and 39).
153 op. cit. note 17 above.
Haemophilia: Recent history
the literature extremely well, being a great scholar, and knew about the South
American paper 154 and said, 'Go and do it again'. Following that they got in
touch with Rosemary Biggs and Macfarlane and that resulted in the original
Christmas paper in the Christmas issue of the British Medical Journal in 1952. 155
And it was interesting also that people like Dacie, Rosemary Biggs and Gwyn
Macfarlane were not the sort of scientists who fought with each other for
priority. If they had a problem they got together and that's exactly what
happened over Christmas disease. It's a very good message
to us all.
Lee: I think there's another twist of the tale of Mr Christmas. Rosemary
Biggs 156 told me that nobody believed that his name was Christmas for a start,
because it happened to appear in the Christmas edition of the British Medical
Journal 57 and they thought it had all been made up. The rather sad thing, which
probably summarizes what we have been talking about in the first part of this
afternoon, is that I recently was participating in a meeting with a physician
from Canada, called Jerry Teitle, who looked after Mr Christmas in his last
years. Mr Christmas died a few years ago of HIV and I think that really
illustrates what a short time span we are considering: first the disorder was
described, the treatment was evolved, and the poor man actually died from the
side-effects of that treatment. We are going to have to break for tea now in the
next room, where there are some amazing photographs of Dr Bidwell in her
younger days with her assistant Ross Dike (Figures 1-8). It's due to Mr Dike
that we have these beautiful photographs, because when the laboratory was being
tidied up at Oxford, he rescued them and put them in his loft.
Ingram: Just before we go may I finish the story about the name of Christmas
disease? A gentleman from Leeds wrote to protest at this, and so Biggs and
Macfarlane wrote back in the next British Medical Journal^ to say that if they
hadn't used that name they would have made up an enormously long name 159
which was much less easy to deal with, but they gave an undertaking that if they
found a precursor factor they would not call it Christmas Eve factor!
15 See note 16 above.
155 op. cit. note 18 above.
156 op. cit. note 2 above.
157 op. cit. note 18 above.
158 See Collins D H. (1953) Christmas disease. British Medical Journal v. 97. Kemp P R. ibid.
Biggs R, Douglas A S, Macfarlane R G. ibid. 221.
Haemophilia: Recent history
EvanS: I also wanted to make one little comment, to remind some of the
people who aren't as old as the rest of us, that in those days when you had to go
to the slaughterhouse to get reagents to do laboratory work, you also had to
make your own apparatus. You couldn't go and buy an amino-acid analyser, or a
gas chromatograph off the shelf, you had to get the parts yourself and put it
together and that's what the bits of Meccano were referring to. If you wanted
to make a chromatograph, you had to go to the workshop and get a tube, and cut
it to the length you required, and that I think is worth remembering.
Lee: Can we now look at more of the organizational aspects of haemophilia
both from the healthcare delivery side, the UK Haemophilia Centre Directors
Organization, its beginnings, and the Registry at Oxford. Also the
Haemophilia Society and how it grew up and how it interrelated with the
Haemophilia Centre Directors Organization, and the delivery of care.
Although we are primarily thinking about haemophilia in the context of Britain,
we have to think a little bit about the influences that Britain had on the World
Federation of Hemophilia, because they were quite significant. We are also
going to discuss what we really don't like to think about too much, but sadly
have to think about a lot, and that is the contamination that blood products have
brought upon the haemophilic population and the enormous change in so many
ways that that has influenced. Then, finally, because I think it would be so sad
to end this afternoon
1 See note 126 above.
Figures 1-8. Preparation of animal antihaemophilic globulin in 19S5
1. Animal blood is collected at the slaughterhouse and brought to the laboratory by Ethel Bidwell and her assistant Ross Dike.
; : «ti;i: : r
It ' i
2. The blood is centrifuged to separate plasma from the red cells.
3. Plasma is removed by suction.
4. The plasma is again separated by centrifuging. It is cooled and the active factor is precipitated by adding phosphate bujfer.
5. The purification is carried a stage further by another precipitation, with sodium citrate.
6. The precipitate is collected by centrifuging and the supernatant fluid containing impurities is discarded. The precipitate is dissolved in saline.
7. Most of the addec
I to the instability of material, this must be done rapidly. The apparatus is shown.
8. Preservation by freeze-drying.
Photographs kindly provided by Mr Ross Dike, processed and mounted by him. Permission granted to reproduce photographs,
Dr Ethel Bidwell and Mr Ross Dike, 1999. ©Mr Ross Dike, 1999.
Haemophilia: Recent history
on a dismal note, I want to focus a little bit of attention on the early
development of recombinant products which, of course, is what we all want to
treat our patients with in 1998. I am going to ask Dr Rizza to try and set the
scene. How did the Haemophilia Centre Directors Organization come about?
Rizza: Before tea Clifford Welch talked about treatment as it was in the 1930s
and the 1940s and he mentioned Timperley's egg white and a patient called
Frank Smith. Timperley's egg white were little tablets, these [holding
some] the date of which, I think, was 1949. A bit out of date now. I am going
to be provocative and suggest that, in fact, this is to some extent important in
the development of haemophilia care, because Mr Frank Smith, and some other
haemophiliacs at that time, were very conscious of a lack of treatment or any
support for haemophilia. I know Mr Smith made a nuisance of himself — he
wouldn't mind me saying that - by going to the Ministry of Health on many
occasions, and to the Medical Research Council, asking them to make this very
important material [i.e. Timperley's egg white]. But they could never find any
scientific evidence for putting any effort into that, so he began to make it in his
kitchen at home. My recollection is that this material required fuming
hydrobromic acid for its manufacture from egg albumin and on one occasion it
blew up in his face in the kitchen and he was scarred for life thereafter because of
his acid burns. But I think the consequence of the inception of the National
Health Service, and people like Frank Smith constantly asking for help, was
that Sir Weldon Dalrymple-Champneys, 162 who was a Deputy Chief Medical
Officer, wrote to Professor Macfarlane in Oxford and to Dr Wilkinson 163 in
Manchester suggesting that something should be done for haemophiliacs. The
time had come to sit down and make plans. So they had a little meeting, a very
informal meeting in early 1950, and thereafter several meetings were held with
other interested doctors. They wrote around to find out who was interested in
haemophilia and they got a small group together and they began holding more
formal meetings to discuss what could be done. And of course in those days
there was nothing that could be done really. There weren't even diagnostic tests,
or at least reliable ones. So they agreed that they should give advice to the
patients on how best to help themselves, advice to the GPs on how best to help
the patients and also to educate the general public, and in particular employers,
161 op. cit. notes 129 and 130 above.
162 Sir Weldon Dalrymple-Champneys FRCP (1892-1980) was President of the Haemophilia
Society for 27 years. He joined the medical staff of the Ministry of Health in 1927 and became
Deputy Chief Medical Officer in 1940.
163 op. cit. note 76 above.
Haemophilia: Recent history
about the needs of haemophiliacs. And that's how it started and I like to think
that it probably started because of the insistence by some patients on the value
of this material, egg white.
Thereafter, the organizing group became larger, and it was agreed that
certain regions should have centres to look after haemophiliacs. The MRC got
involved in the early 1950s and promoted and funded work on the manufacture
of factor VIII. Thereafter, the Ministry of Health took over the organization of
care, but all the time there was a nucleus of centres in regions throughout the
country who were offering care of a kind. It was mainly supportive, there was
no therapeutic material available, but they were getting together the core of
As time went on and factor VIII became available more widely,
especially by 1 972 when the first large pool concentrates began to come into the
country, it was seen then that there was a need to formalize the organization of
the care a little more. In 1968 the first meeting of doctors who were interested
in haemophilia met in Oxford. There were 26 doctors who turned up and we
had an afternoon party and, I think, there were one or two lectures given, a lot of
exchange of ideas, and exchange of worries about haemophilia care, and the
feeling was that really this was so useful that we should meet every year
thereafter to discuss the problems of haemophilia. Simple things like how
many staff you require to look after 100 patients or 50 patients, what services,
what nurses do you require. This is how it started in 1968 and since then, yearly,
the Directors of the Haemophilia Centres up and down the country have met at
different places around the UK just to do what I have said: discuss problems,
learn from each other and from people from abroad. Eventually scientific
sessions were built in so that foreign experts could come and tell us what was
happening in other parts of the world, and this was the way the organization of
haemophilia care in this country started.
Lee: Can you tell us when the Registry first came about?
Rizza: In 1968, right after the first meeting. After the first meeting it was felt
that without information on the numbers of patients, what kind of treatment was
being used up and down the country, what kind of complications were being
met, how many cases were dying, it would be very difficult to promote better
care and better organization and so on. So from the very early days annual
returns (Rosemary Spooner is here, she helped to set it up) were received from
Haemophilia: Recent history
all the Haemophilia Centres in the country. They were analysed, reports were
written, and those reports were sent back to the different Haemophilia Centres,
as well as to the Department of Health and to the fractionation laboratories.
The fractionation laboratories had to know the size of the problem as they were
going to be manufacturing the concentrates necessary for treatment. The
Registry has been going for 30 years now.
Lee: In the interview with Dr Biggs last week, she described in vivid detail
this first meeting and she said, 'Well I decided to have a party. Everybody
likes to come to a party. And I invited to this party everybody who knew
anything about haemophilia at that time. I was a lady, and ladies were allowed
to organize parties.' And the other thing was when we went on to talk about the
organization and having a chairman and things, she said, 'I was never the
chairman, I don't think there is any point in being a chairman. Chairmen don't
have any power. The power resides in the person who writes the minutes, and I
write very good minutes.' 1 5 Now can you perhaps, Alan, tell us when the two,
the Haemophilia Society and the Organization, interacted.
Tanner: Yes, that was at the beginning as Dr Rizza says. He mentioned the
name of Sir Weldon Dalrymple-Champneys who was a key person in
encouraging people with haemophilia to come together to meet for mutual
support, sharing views about treatments or the paucity of treatments, to help
each other in terms of financial support if that seemed to be necessary. Those
small beginnings in the 1950s were mostly in people's houses, just a small
number getting together. It began to expand and eventually in the 1960s they
thought about looking for some kind of base where they could congregate much
more frequently and have an office from which they could operate. So the older
members, the old hands, will recall the famous fire station in Southwark. It was
surplus to requirements, let me add, it was a building which was made
available, and that was the beginning of an organization for the Haemophilia
16 Rosemary Spooner (b. 1937) was Secretary to the MRC Blood Coagulation Research Unit
from 1961 to 1967 and Secretary/Research Assistant to Dr Rosemary Biggs, at the Oxford
Haemophilia Centre from 1967 to 1977. Since 1977 she has had an NHS appointment as
Research Assistant/Data Analyst at the Oxford Haemophilia Centre and has been Honorary
Administrative Secretary to the United Kingdom Haemophilia Centre Directors
Organization since 1988. She is co-author to several publications including Biggs R, Spooner
R J D. (1977) Haemophilia treatment in the United Kingdom from 1969 to 1974. British
Journal of ' Haematology 35: 487-504. idem Haemophilia Centre Directors' annual statistics for
1975. ibid. 36: 447-449. idem (1978) National survey of haemophilia and Christmas disease
patients in the United Kingdom. Lancet v. 1143—1144.
165 op. cit. note 2 above, 770.
166 See biographical note 162 above.
Haemophilia: Recent history
Society, manned entirely by volunteers and that was a very, very important
aspect of the whole organization. It was done by volunteers supporting each
other and beginning to become rather aggressive in their style in relating with
their doctors and dealing with the Government and so on. They began to
organize one or two campaigns, and now the society is well organized as a
One of the first campaigns they ran was to do with the provision of
transport. There was some deadly mechanism which some will recall. It was a
tricycle which was made available for those who were disabled and it was
lethal. They managed to get none other than Graham Hill, who was quite
famous as a racing driver then, who took his life in his hands by testing it. They
assembled together MPs and Graham Hill drove this erratically so that it
overturned and so he was able to demonstrate that it was not suitable for people
with haemophilia. That was the beginning of that kind of campaigning
movement. Volunteers were operating from this old fire station, which was a
good place to meet and to lodge papers, because by then they began to
accumulate a certain amount of files and papers and so on.
The next move was when the lease of that dilapidated building expired,
and they moved into much more palatial surroundings in Trinity Street in
Southwark, which many will remember, again run entirely by volunteers. But the
Organization was developing to such a degree there in the 1 960s that they found
it was no longer satisfactory for people to be keeping papers at home; letters
got lost and were never answered, so they managed to recruit a part-time
secretary, Irene Watson, who came in two mornings a week to deal with the
correspondence. Then, moving on quite rapidly to the end of the 1960s,
beginning of the 1970s, they felt that they were in need of some kind of full-
time assistance. But still pre-eminently, it was a volunteer organization and they
could not see their way to appointing a general secretary or administrator. The
first full-time person appointed was a social worker, Victoria Stockford, who
operated from 1975 to 1980. It was the first sign of the introduction of
professionalism into the society. All this is keeping pace with the development
of medical care. Because now, towards the end of the 1960s, cryoprecipitate
was available but not in sufficient quantities, so they began again to adopt that
lobbying stance, pressing their centres, which were being established by then,
pressing the Government and so on, and then all that led into the development
of the concentrates. Again, a major lobbying function.
In the 1970s I was invited into the presence of the Minister of State for
Health, Dr David Owen, because one of our points for lobbying at that stage
was the disquiet about the purity of the blood products that were coming from
America. We had seen stories on the television of blood donors in the
Haemophilia: Recent history
United States being recruited from Skid Row and we spoke very forcibly to
Dr David Owen to let him know that we were not prepared to accept the risk of
hepatitis coming from the blood products issued from the United States. All
this was rather prophetic when you think back on those days and the ways in
which things have changed.
From then on, the society having got its first taste of a professional
administrator, found it wasn't so dangerous after all: they could still not see
their way to appointing an executive secretary or a general secretary who would
take over the organization, they still had the thought of volunteerism in mind,
so they appointed a coordinator, one who would not be too firm, to the point of
excluding them from running the society, but would coordinate the efforts of
the volunteers. The person appointed was David Watters who came into the
office in 1981 and served with us until 1993 with great distinction. I think when
we come to write the history of the Haemophilia Society, a very, very
significant contribution will be shown to have been made by David Watters who
really did introduce that note of professionalism that was required to pull the
whole organization together. From then on, it began to be recognized by
Government departments, by centre directors and so on, as the instrument by
which the voice of people with haemophilia could be expressed.
I'll go on later perhaps to say something about the way in which we have
continued campaigning with the society, the way in which we have dealt with
the Government in matters like HIV infection, with the supply of blood
products and so on. But the society has also been very keen to be involved in the
whole matter of the designation of centres, and the facilities provided by
centres. At the same time they have had their eye not only on the people with
haemophilia themselves, but those within the family, because there was an
increasing concern for the sisters in the family, with the whole matter of genetic
counselling. That has been again a very major contribution made by the society.
Fund-raising came into it very emphatically, of course, because all this required
money. So we've moved from those early days with a part-time secretary to
now quite a
substantial organization where there are specialists attached to it. There is an
HIV worker appointed by the society and a hepatitis worker. That is the state
where we are today.
Lee: Can you just very briefly talk a little bit about the contribution that has
been made towards the World Federation of Hemophilia from a British
Haemophilia: Recent history
Tanner: I was thinking it's a pity Peggy Britten 167 is not with us at this
seminar. She really is the doyenne of all supporters of the World Federation of
Hemophilia. She was responsible for generating an immense amount of
enthusiasm in the national society for people to play a full part in the World
Federation of Hemophilia. The history of that is: at the first meeting in 1963
in Copenhagen there were six national societies represented. Again, they got
together for mutual support, they wanted to know, now that people were
beginning to travel abroad, where they could get treatment, because what was
available was very, very patchy in those days. They wanted to know about the
kinds of treatment available, how to relate with the Government and how to
develop friendships with people with haemophilia in other countries. From that
beginning in 1963, it has now expanded to the point where practically every
country of note has a national member organization which is represented in the
World Federation of Hemophilia, so it's something like 88 on the present
count. There was a particular parallel with the national society. The World
Federation of Hemophilia started in a very amateur way, but was inspired by
the founder, Frank Schnabel 168 who himself was a person with haemophilia and
motivated his peers in the other national organizations. At that time, again,
volunteerism was the key note, but now it is a highly professional organization
which is concerned not only with sharing information but having a particular eye
developing countries, which Peter Jones will be able to speak about. 1 9 That is
mutual support par excellence in seeing that facilities are provided in those
countries which are much less fortunate than ourselves in the provision of
treatment and management.
167 Peggy Britten (1912-1999) was unable to attend the meeting and died shortly afterwards. She
had two brothers who died of haemophilia. Her son, Tony, also a haemophiliac, trained as a
doctor in Johannesburg and later became Medical Director of a large transfusion centre in
New York and Head of the Blood Programme of the League of Red Cross and Red Crescent
Societies in Geneva. In 1965, Tony put her in touch with Katharine Dormandy to help with
surveys into the problems of young haemophiliacs. She later became involved with the
Haemophilia Society and World Federation of Haemophilia. She held the position of London
Secretary and travelled extensively to many World Federation meetings. See Britten P. (n.d.)
Living beside haemophilia in the 20th Century [unpublished manuscript] and note 170 below.
Copies of the tapes and transcript of an interview with Peggy Britten, conducted by Professor
Christine Lee on 19 March 1998, will be deposited with the records of this meeting in the
Contemporary Medical Archives Centre of the library of the Wellcome Institute for the
History of Medicine.
168 Frank Schnabel (1926-1987), a severe haemophiliac, was a Founder of the Canadian
Haemophilia Society and also Founder and First President of the World Federation of
Hemophilia in 1963 when he convened the first meeting of six national societies in
169 Dr Peter Jones wrote: 'The World Federation of Hemophilia is a unique international
organization, administered jointly by people with haemophilia and their relatives, and by
doctors and scientists with an interest in the inherited bleeding disorders. Much of the present
thrust of the their work is targeted at helping people with haemophilia in low economy
countries.' Letter to Dr Daphne Christie, 5 July 1999.
Haemophilia: Recent history
Lee: Yes, maybe I could mention a little bit about Peggy Britten.
Unfortunately, she wasn't able to come today because she has got a terrible
cold, but we are hoping to interview her subsequently. 170 She had a son with
haemophilia who subsequently became the Head of the Transfusion Service in
Canada and she also suffered the death of a brother with haemophilia when she
was quite young. So she was really very involved. She worked as Katharine
Dormandy's research assistant, to research into the educational needs of the
children of the south of England and to that end the Haemophilia Society paid
money for a caravan which was put on the Lawn Road site. 171
Before we move onto what we will spend most of the rest of the time
talking about, and that's contamination, we should hear something from Dr
Sheila Howarth about the MRC and the provision of concentrates.
Dr Sheila Howarth: 172 1 was very surprised that in the course of the afternoon
credit was not given where credit was due, because much of the work that has in
fact been described was supported by the Medical Research Council, and pretty
lavishly considering the budget of the time. The MRC Blood Coagulation
Research Unit in Oxford, which was directed by Gwyn Macfarlane, ran from
1959 until Macfarlane retired in 1967, and the work was then continued under
MRC auspices by Dr Rosemary Biggs. It trained a lot of the people who were
seeded out throughout the country; and the Council gave fellowships for people
to go and train there, as some people here will know.
But to go back before that. I moved into the headquarters office of the
MRC in 1964, and there was a haemophilia committee, the MRC Haemophilia
Committee, chaired by Dr J F Wilkinson of Manchester, of which Professor
Ilsley Ingram was a member and could probably tell you much more about it
than I could. When this was disbanded in 1966, its work was taken up in the
main by the MRC Blood Transfusion Research Committee, chaired by Pat
Mollison, which included representatives from England and Scotland and
directors of centres and also representatives of the services. It took haemophilia
on board when the Wilkinson committee was wound up. It hasn't been
mentioned that the MRC actually managed the Blood Products Laboratory for
170 op. cit. note 167 above. See also Britten M I, Spooner R J D, Dormandy K M, Biggs R. (1966)
The haemophilic boy in school. British Medical Journal ii: 224-228. Dormandy K M, Gandy R
H, Britten M I. (1966) Problems of management of children with coagulation disorders.
Bibliotheca Haematologica 26: 171-175. Britten M I. (1967) Haemophilia and its problems.
District Nursing 10: 120-122.
171 The caravan was parked at the old Lawn Road Hospital in 1964, on the site of the present
Royal Free Hospital in Pond Street, Hampstead. It was replaced by the purpose-built Katharine
Dormandy Haemophilia Centre and Haemostasis Unit in 1978.
172 Dr Sheila Howarth FRCP (b. 1920) joined the staff of the headquarters office of the
Medical Research Council in 1964. She retired as Principal Medical Officer in 1980.
Haemophilia: Recent history
the Department of Health, and there was a Managing Committee, which again
was chaired by Professor Mollison. This was a difficult committee because it
had to point out endlessly to the Health Department the increasing need for
blood products, and that really they ought to get on with increasing the
accommodation at Elstree 173 and with the proposed new building. The
Department of Health almost invariably dragged its feet. They were disastrous
meetings. Dr Dodsworth has described very politely what went on. I can
remember one occasion when Dr Biggs and I had to take Professor Macfarlane
as an expert witness from Park Crescent [the MRC Headquarters] , where he was
briefed, by Tube, to a meeting at Elephant and Castle [the Department of
Health and Social Security]. He had claustrophobia. We had the greatest
difficulty in getting him down the escalator and onto the Tube, and having got
him into the building at the Elephant, he stood at the bottom of the lift, dug his
heels in and said he wasn't going to get in the lift. Anyway, we finally got him
to the meeting, and he was our leading witness, so to speak. But the Department
in England did drag its feet, and it was a disastrous period.
In Scotland, they took notice of the advice which was given by the
committees of the MRC and phase 1 of the redevelopment of the Royal
Infirmary in Edinburgh included the fractionation laboratory, 174 so they were
prepared when nemesis came. My information [which came from the office of
the Haemophilia Society] was that in 1990, at the time when my haemophilic
nephew died HIV positive in this country [England], of the 600 known
haemophiliacs in Scotland, only 27 were known to be HIV positive, and most
of these were suspected of having acquired the infection by association with the
drug fraternity in Edinburgh. 175
The other point perhaps I should pick up - I don't want to go on - is the
Haemophilia Register. When I went to the MRC in 1964, one of the first things
that happened to me was that two card-index files arrived on my side table,
covered with dust, and there they continued to accumulate dust. This was called
the Haemophilia Register and it had been set up by the MRC. People used to
submit cards to the relevant section of the office about additional cases of
173 See note 62 above.
17 The Scottish National Plasma Fractionation Centre was housed in the Edinburgh Royal
Infirmary. See Girdwood R H. (1990) Fifty years of an organized blood transfusion service in
Scotland. Scottish Medical Journal?) 1 !): 24-28.
175 Dr Charles Rizza wrote: 'Is it being suggested that those Scottish haemophiliacs were drug
users? Or is it being suggested that the infected drug users gave blood which infected the plasma
supply used for fractionating factor VIII in Edinburgh? I wonder how many drug users are
volunteer blood donors. I think the source of infection in Scotland was probably no different
from that in England. Even if the evidence is cast-iron that drug users were the source of
infection, I think it should be made clear that the haemophiliacs themselves were not "drug
users".' Communication with Dr Daphne Christie, 3 July 1999.
Haemophilia: Recent history
haemophilia as they were diagnosed. We tried to get the Health Department to
put this on a more regular footing and we met with intense resistance. Finally
we managed to get it handed over in 1966, when at Park Crescent [MRC
headquarters] we had a party, as it had been such an uphill battle. I may add
that the Register having sat on my side table, the Department then regarded it
as something that had security risk implications, and they were said to have
taken it down to the basement at the Elephant and Castle and locked it in the
safe. I don't know what happened to it after that.
Anyway, you can see that, in fact, the MRC was extremely active in this
field, in not a passive but an active role. If we failed I think it was due to the
fact that we could not push the Elephant [Department of Health], which has a
period of gestation anyway of about 18 months, into any urgent action. I think
perhaps the history of the MRC's part in this ought to be gone into in more
detail, because it's a long time ago. I retired in 1980 and I am totally out of
touch with what went on after that.
Lee: Before we go to Dr Dodsworth, this Register, did it come into your
Rizza: No, no. It must be locked away somewhere.
Howarth: It's probably still locked away in the safe at the Elephant and
Dodsworth: I wonder if I can make a slightly sympathetic comment with
respect to the British Transfusion Service. The Fractionation Centre at Elstree
never had control over its own plasma supply until the National Blood
Authority was founded in 1993. 17 Consequently, although the facilities for
making factor VIII were available, there was never enough plasma with which
to make it. The situation was always somewhat easier in Scotland where the
main concentration of population, and thus of blood donors, is close to the
country's main transfusion centre [in Edinburgh]. When I was working in
Manchester in the late 1960s we had no factor VIII at all and were aware that
there seemed to be plenty in Scotland: we were very jealous.
176 A history of blood transfusion services in the UK is given in Dodsworth H. (1996)
op. cit. note 99 above.
Haemophilia: Recent history
Mr ROSS Dike: 177 I would just like to make a further comment about the
support we had from the Medical Research Council which is not often realized.
Nearly all the advances, both in biochemical research and also in fractionation
processes, are also consequent on the advances in the equipment that's used. In
other words, the design and the building of novel equipment or the
modification of commercial equipment. In this way when we moved up at the
end of 1958 from the Radcliffe Infirmary, Oxford, into the MRC Blood
Coagulation Research Unit at the Churchill Hospital, Oxford, we were very
strongly supported by the MRC Central Workshops which occupied a building
in the same hospital [the Churchill Hospital], and this led to a lot of advances,
including such things as the successful separation of factor VIII from
fibrinogen, 178 the equipment in which the first column fractionation of DEAE-
cellulose factor IX was carried out, 179 etc. I could go on for half an hour
enumerating these things. But it was in this way that part of the success of our
research was due to the proximity of this workshop. This was proved later on
after the retirement of Professor Macfarlane. We separated into three distinct
units, one of them being a plasma fractionation unit, which I worked in. We d i d
not have adequate engineering or electronic facilities after the MRC Central
Workshop was closed, so we built and staffed our own workshops for the design,
development, commissioning and modifying equipment and services, and the
provision of a planned preventive maintenance programme. I think that the
importance of this should be acknowledged.
Bangham: I'd like to point out again that all the biological standards
contributing to the field were made in the Division of Biological Standards at
177 Mr GWR Dike (b. 1932) started working as Dr Bidwell's assistant in Dr Macfarlane's
Haematology Research Unit, Radcliffe Infirmary, Oxford, in 1954 — in time to be involved in
preparing the first dose of bovine antihaemophilic globulin which was successfully
administered to a haemophilic patient. The Unit was taken over by the MRC (in April 1959) as
the MRC Blood Coagulation Unit, and moved to the Churchill Hospital, Oxford, when Dike
became an MRC Technical Officer. On Professor Macfarlane's retirement in 1967, Dike was
involved in the planning and supervision of the subsequent building of the Plasma
Fractionation Laboratory on the same site, and then its subsequent expansion. Dike was Safety
Officer from 1974 and retired in 1992 as a Higher Professional and Technological officer
(MRC) and had also been on secondment to the NHS since 1969.
178 Bidwell E, Dike GWR, Denson K W E. (1966) Experiments with factor VIII separated
from fibrinogen by electrophoresis in free buffer film. British Journal of Haematology 12:
179 Dike GWR, Bidwell E, Rizza C R. (1972) The preparation and use of a new concentrate
containing factor DC, prothrombin and factor X and of a separate concentrate containing
factor VII. British Journal of Haematology 22: 469-490. Mr Ross Dike wrote: 'This paper has an
illustration of the original large-scale chromatography column, and the refractometer that was
invented and built for this work since no suitable commercial columns or in-line equipment
were available.' Letter to Dr Daphne Christie, 22 March 1999.
Haemophilia: Recent history
the National Institute for Medical Research until 1974. That was all work
under the MRC.
Douglas: Dr Howarth has mentioned the relatively low incidence of HIV
infection amongst the Scottish haemophiliacs. One name in that connection
should be mentioned, John Cash. 180 He was able to obtain agreement
amongst the Scottish blood transfusion directors to favour investment in
the plasma fractionation unit in Edinburgh and so reduced the need to use
As regards the registration of haemophilia, I remember in around 1960
filling in those green cards which Dr Howarth described earlier for issue to the
patients and lodging the names with the MRC office in London.
Lee: It's very interesting how Scotland is always so different. I mean the
difference remains to the present day, when the Government gives them
£2 million so that they can introduce recombinant factor VIII.
I am going to change topic now and I think we need to spend some time
hearing about the beginnings and the effects that viral contamination, and the
side-effects of treatment, had on haemophilic patients, the people treating them
and the whole way really we practise medicine. I think, Peter, you played quite
a part in this in the early days. Can you start at the beginning and give us a feel
for when the thing first began to hit.
JoneS: I think you have to set what has happened in the context, firstly, of a
rare disorder affecting a small number of the population of the United
Kingdom, hence some of the resistance to the views of the MRC, the
Haemophilia Centre directors and the patients' groups early on. You also have
to set it against the scenario of how enthusiastic we were once effective
treatment became available. Previously we had not been able to treat these
little boys who were missing their schooling, had no career to look forward to,
were growing up illiterate, were growing up crippled. We had nothing. We had
enough factor concentrate to deal with the major surgery and that was really
about it. Cryoprecipitate opened our eyes and then the concentrates came. We
couldn't use the animal concentrates because they were antigenic, they stopped
working after a while, so we turned instead to human concentrates. We knew
from the beginning that we were transmitting disease, we knew there was
180 Professor John Cash FRCS FRCPEd FRCPath was National Medical Director, Scottish
National Blood Transfusion Service headquarters in Edinburgh from 1988 to 1996 and
President of the Royal College of Physicians in Edinburgh from 1994 to 1997.
Haemophilia: Recent history
something then called serum hepatitis, we now know it as hepatitis B, after the
Australian antigen was discovered. 181 We knew that hepatitis B was in those
concentrates and the companies knew that hepatitis B was in those concentrates.
The first outbreaks of hepatitis B in the haemophilia population of the United
Kingdom in the early 1970s were because of dumping of concentrates which
would not have passed the Food and Drug Administration (FDA) regulations
in the United States of America. Even that did not blunt the enthusiasm for
treatment, because we moved on, as David Evans has said, to home therapy and
from there to prophylaxis and to the prevention of haemophilic arthropathy. We
also knew there was another virus in the concentrates which we then called non-A
and non-B hepatitis and we now know as hepatitis C, 183 but all the evidence then
from around the world then was that this too produced a chronic disorder which
might result in ill-health in a few people. It was not thought to result in a
devastating disease of the liver which would kill more than a few people. And
it was worth trading that off for the improvements in haemophilia care. We
didn't know anything about HIV, or AIDS, and this observation is important
because in the early 1980s there was a school of thought, particularly amongst
people who were campaigning for compensation, that we'd known about AIDS
It is very salutary in talking about the history of haemophilia treatment,
and the history of medicine in general, to realize that advances in care are rarely
straightforward. There's a cartoon by Matt on the front of the Daily Telegraph
today and I paraphrase it, 'We have known about spongiform encephalopathy for
a long time, but it has taken us two years to know how to pronounce it.' In the
early 1980s there was this feeling that we had all known that there was another
virus there, and if we look at some of the features at the beginning of the HIV
epidemic and what we now know about new variant CJD (nvCJD), it's a little
chilling. First of all the timing. In every decade of modern haemophilia
therapy a new virus has appeared. We have been through the hepatitis alphabet of
A, B, C, delta, E, and we are down to G. We have found parvovirus. Every
decade brings a new virus: so HIV in the early 1980s, 185 then hepatitis C
181 Baruch Samuel Blumberg won the Nobel Prize in 1976, jointly with D Carleton Gajudsek,
for his discovery of the Australian antigen associated with hepatitis B virus. See Blumberg B S.
(1984) The Australian antigen story. In Millman I, Eisenstein T, Blumberg B S. (eds) Hepatitis
B: The virus, the disease, and the vaccine. New York: Plenum Press, 5-31.
182 The Food and Drug Administration (FDA) of the USA (founded in 1938) is the premier
drug regulatory organization in the world, inspecting and licensing the manufacture of foods,
cosmetics, pesticides as well as human and veterinary medicines.
183 See note 92 above.
18 op. cit. note 88 above.
185 op. cit. note 87 above.
Haemophilia: Recent history
recognition in the early 1990s, 186 and now a question mark. Initially, HIV and
now nvCJD had well-defined patient groups; with CJD we have the growth
hormone group. 1 7 Animal connections are obvious with nvCJD, the green
monkey with HIV. With CJD we don't know where the infection is, there isn't
a test; the same for HIV was true. Query - is it transmissible by blood?
With HIV, we realized that we had got a problem after the description of
the first cases in 1981. The Haemophilia Centre directors thought very long and
hard, and thought that one in a thousand people who had been transfused with
contaminated products would develop AIDS. One in a thousand. Again it was
something to be concerned about, but perhaps to put on one side in favour of
continuing treatment. We didn't know any means of removal. Heat treatment
had been tested to try to get rid of hepatitis viruses, but in fact if it had been
tested heavily in the 1970s it probably would have been rejected and not
thought of for HIV, because it did not stop transmission of hepatitis. With
CJD, as was the case initially with HIV, there's no individual donor testing.
There's no surrogate testing. There's a very long incubation period which is
what caught us out with 'the one in a thousand' at the beginning of HIV. CJD is
a deadly disease, there is no known treatment. Now with HIV we've moved on
and we have got long-term survivors. Both CJD and HIV have produced terrific
dilemmas for the authorities. You have only got to think of beef on the bone,
and the scepticism of the public. It's a catch-22 situation, 188 there is enormous
publicity, much of it ill-informed. The media like to think in terms of black
and white, there is no grey area in the middle. When doctors say they don't
know, or scientists say they don't know, it adds to the uncertainty. So there is a
tendency for the Government, and we have already heard the MRC perspective
about transfusion, 189 to follow a course of action without telling those at the
leading edge. That was certainly true at the beginning of HIV and may now be
true in the case of CJD in the case of the farmers. At the beginning of the HIV
epidemic I thought that it must have been almost like being in World War I
when the generals were doing one thing and the men were all doing something
else. I felt very much like the brigadier in Dr Who because I felt that I had to
be pragmatic and act, but there was nobody to turn to; there was no leadership
whatsoever from central Government or the Department of Health. In fact, if
186 See note 92 above.
187 Knight R, Stewart G. (1998) The new variant form of Creutzfeldt-Jakob disease. FEMS
Immunology and Medical Microbiology 21: 97-100. See also Lee C A (1996) Transfusion-
transmitted disease. Baillieres Clinical Haematology 9: 369-394.
188 Catch-22 - A no-win situation. 'Orr would be crazy to fly more missions and sane if he
didn't, but if he was sane he had to fly them. If he flew them he was crazy and didn't have to; but
if he didn't want to he was sane and had to.' Heller J. (1961) Catch-22, Ch. 5. Leicester:
189 See discussion on page 59.
Haemophilia: Recent history
anything, in the initial years there was antagonism. There was an enormous
amount of money spent fannying around, when all that was really needed was to
put every Haemophilia Centre director and the small number of other people
working with the early groups affected by HIV, particularly in London and
Edinburgh, onto a jumbo jet and take them to the United States to teach them
how to look after people with AIDS and prevent transmission. 19 °
Then followed, of course, the discovery that the majority of our severe
haemophilic patients were affected, and I wish the story that you gave us about
Scotland was true, but it isn't; there were many more patients in Scotland
infected and infected with Scottish product. m Then there followed a campaign
for 'recompense', we called it, because 'compensation' suggested no-fault
compensation and Government blocked that, of course, for people with
haemophilia and their families and the survivors. 192 And that led to the
Macfarlane Trust with the first £10 million which came from Mrs Thatcher.
One afternoon at three o'clock she suddenly said, 'We'll do it, there's the
money'. Why she did it, we have never discovered.
Lee: Didn't that happen when John Major came in?
JoneS: No. The first £10 million for the Macfarlane Trust came from
Margaret Thatcher. The later payments, two extra payments to people with
haemophilia, were from John Major's Government and that came after
prolonged litigation which was very, very uncomfortable. In medical practice
when you are being litigated against, normally the patient isn't your own
patient. You can push the patient, if that is the right way of putting it, onto a
colleague. But in this case, you couldn't. So we had Haemophilia Centre
directors looking after patients and families, and at the same time being
190 Dr Peter Jones wrote: 'It should be remembered that the haemophilic population was hit by
HIV first, about two years before the epidemic became apparent in the general population,
because of the direct inoculation of the virus in treatment. So the directors were at the leading
edge of the epidemic in this country.' Letter to Dr Daphne Christie, 5 July 1999.
191 See Simmonds P, Beatson D, Cuthbert R J, Watson H, Reynolds B, Peutherer J F, Parry J V,
Ludlam C A, Steel C M. (1991) Determinants of HIV disease progression: six-year
longitudinal study in the Edinburgh haemophilia cohort. Lancet 338: 1159-1163.
192 The term 'recompense' was used because the Government would not support no-fault
compensation. Dr Peter Jones wrote: 'The initial campaign in 1987 was orchestrated
principally by David Watters [see page 57] and his colleagues in the Haemophilia Society and
Dr Jones in Newcastle. Intense lobbying of Parliament was undertaken and included the
distribution of a booklet, This is URGENT. Haemophilia and AIDS, which detailed the
hardship being experienced by people with haemophilia and their families, to members of
both Houses and to the media.' Letter to Dr Daphne Christie, 5 July 1999. See Jones P. (1987)
Hidden victims of AIDS.
The Times (9 October 1987). idem Haemophilia, AIDS, and no fault compensation.
British Medical Journal!*) 1 ): 944-945.
Haemophilia: Recent history
litigated against for HIV infection and subsequently AIDS, and that took
personally two years out of my clinical life. I had to shut my door and just go
through all the records for litigation. Some of my personal record of the time
has already been published. 193 That still continues with hepatitis C of course.
God willing, we are not going to see CJD as a transmittable disease to the
haemophilia population. Hopefully it will not be long before we know the risk
factors, because the risk committee and SEAC, the Spongiform
Encephalopathy Advisory Group, reports to ministers in March, so we may have
a better idea then. 1 As Alan [Tanner] said, the Haemophilia Society has
grown into a very well-presented professional lobbying body, but in some cases,
and in the case of the World Federation as well, it has left in its wake
difficulties, some bitterness, some doctors who don't want to know anything
about haemophilia ever again, and this continues even today with HIV. Thirty
of our colleagues in France have been charged officially with poisoning and
stand trial to spend the rest of their lives in prison. 195 These are colleagues just
like people sitting in this room, who I know perfectly well behaved just as we
did at that time.
Lee: One is a Professor of Transfusion Medicine in this country.
JoneS: I see Jean-Pierre Allain 196 was invited to the meeting and couldn't
come. He has already been in prison for his role in the French HIV epidemic
and, in Japan, colleagues have also been put in prison for their involvement with
HIV and still problems exist. So young physicians, young haematologists, are
reluctant to treat people with haemophilia because they are frightened that they
will be embroiled in litigation and difficulties in their professional lives. So
the sadness of HIV from the professional point of view is still with us, and I
193 Berridge V. (1996) op. cit. note 90 above, for example pages 38-40, 62.
19 Dr David Tyrrell wrote: '...There was the opinion from SEAC [Spongiform
Encephalopathy Advisory Committee, also known after its Chairman as the Tyrrell
Committee, see note 203 below] that there was a theoretical risk of new variant CJD from
blood. They made recommendations on sourcing and processing of blood products'. Letter to
Dr Daphne Christie, 13 March 1999. See a summary of the meeting held on 9 March 1998, in
MAFFNews 119/98, 25 March 1998.
195 Butler D. (1994) Mitterrand asked to pardon doctors in HIV blood scandal. Nature 367: 206.
Anonymous. Contaminated blood continues to boil. ibid. 301.
196 Professor Jean-Pierre Allain, Professor of Transfusion Medicine in Cambridge, and
Director of the East Anglian Blood Transfusion Service, was sentenced by the French Courts to
a term of imprisonment when he was working in Paris in 1984—1985. His alleged crime was to
have done too little to prevent the transmission of HIV to haemophiliacs. See Carrell R W,
Peters K, Cash J, Mollison P L (and 33 others). (1993) Imprisonment of J-P Allain. Lancet 343:
244. Lachmann P J, Bellingham A J, Banatvala J, Carrell R, Hoffbrand V, Wagstaff W. (1993)
Statement of the Royal College of Pathologists on the matter of Professor Jean-Pierre Allain:
19 November 1993. The Bulletin of the Royal College of Pathologists: 84: 3-4.
Haemophilia: Recent history
don't really need to say what sadness there has been in the patient population,
because it has been dreadful. We have seen three generations now of patients
affected and in the face of all this our Government, both the Conservatives and
the Labour Party, have refused to endorse the unanimous opinion of the
Haemophilia Centre directors that recombinant factor VIII and now factor IX
is probably safer than the plasma products and therefore must be the treatment
of choice for people with
Lee: Thank you, Peter. Before we move onto recombinant [factor VIII and
factor IX] for the last part of this there are two things I would just like to
encourage along the way. This is a horrific story but alongside that horrific
story is a good story, in that the life expectancy for somebody with
haemophilia in the late 1930s was 20 years. And this came up very strongly in
the conversation we had with Dr Biggs. We were talking about the school at
Treloar 197 and I said I had a number of adult patients who were at Alton, and
sadly they were ones who had died of AIDS, who'd known each other when they
were all boys together at Alton. She responded by saying, 'Of course, the next
thing that started to crop up was they started to get jaundice'. Dr Biggs
published on jaundice in 1974 198 and, I think, was probably the first person who
actually put into print this complication. And she said, And what we felt at the
time was that they were better alive and having jaundice, than dead with
haemophilia'. 199 1 think that it is important that although this terrible thing has
happened, alongside it has developed good treatment and we'll hear a bit more
about that in a minute from Ted [Tuddenham] .
Charlie [Rizza], before we leave HIV, I hesitate to say this, but from the
haemophilic patients who'd been infected, a lot of science has come which has
actually helped our understanding of the natural history and the biology of
HIV. Would you like to talk a little bit about those data and how they've been
published, and collated, and helped our understanding.
197 The Lord Mayor Treloar Hospital and College at Alton accepted pupils with crippling
diseases and nearly a third of the boys at the college were haemophiliacs. See Gaumont British
Instructional (1945) A Job Well Done (Lord Treloar Hospital and College in Alton, Hants).
Videocassette copy, 1989, Handlist number 183, Wellcome Trust Video Library. See also
Britten M I, Spooner R J D, Dormandy K M, Biggs R. (1966), op. cit. note 170 above.
198 Biggs R. (1974) Jaundice and antibodies directed against factors VIII and IX in patients
treated for haemophilia or Christmas disease in the United Kingdom. British Journal of
Haematology 26: 313-329.
199 op. cit. note 2 above, 772.
Haemophilia: Recent history
Rizza: This stems largely from the organization of care, the registration of
information, the gathering of data. We were in a very strong position in this
country, compared with other countries, in that we had a very good database to
start with. Very easily we picked up information on the prevalence and
consequences of HIV, and along with the people working with Sir Richard
Doll worked on the long-term effects, and the effects of age for instance at
the time of infection. But we also managed to scupper the story which was being
put about by some very serious people in the United States, that HIV had
nothing to do with AIDS and it was a 'bystander effect' 201 and it was this thing
called 'lifestyle' which caused AIDS. No-one could explain to me what the
lifestyle was of the wife of a haemophiliac who had got AIDS or the lifestyle
of a newborn babe who had got it from his mother, the wife of a haemophiliac.
So the data we collected was valuable in that respect and probably put an end to
that story. 202 It hasn't surfaced again. It tends to come up when Professor
Duesberg is asked to speak. It's my own personal view that medicine seems to
stumble from one disaster to the next. All the way through it has been like that.
You develop what you think is good therapy and you find that a significant
number of patients suffer as a consequence, but at the end of it there's been a
little bit of advance. It is a shame that people have to suffer to get there and this
is my own personal feeling, others may not think that. All new therapies are
potentially dangerous, I think, and have to be used with great care.
Lee: One of the really good things that came out of HIV was a real push to get
a safe product and I suppose in the beginning it was sterilization, but then there
was the push to move to recombinant.
200 Professor Sir Richard Doll Kt CH OBE FRCP FRS (b. 1912) was Regius Professor of
Medicine at the University of Oxford from 1969 to 1979, now Professor Emeritus. He was
Chairman of the Adverse Reaction Sub-Committee, Committee on Safety of Medicines, from
1970 to 1977 and has been Honorary Consultant, Imperial Cancer Research Fund Cancer
Studies Unit, Radcliffe Infirmary, Oxford, since 1983. See Darby S C, Rizza C R, Doll R,
Spooner R J, Stratton I M, Thakrar B. (1989) Incidence of AIDS and excess mortality associated
with HIV in haemophiliacs in the United Kingdom: report on behalf of the directors of
haemophilia centres in the United Kingdom. British Medical Journal 298: 1064-1068. Darby S
C, Doll R, Thakrar B, Rizza C R, Cox D R. (1990) Time from infection with HIV to onset of
AIDS in patients with haemophilia in the UK. Statistics in Medicine 9: 681—689.
201 Professor Peter Duesberg, a Californian molecular biologist, claimed no connection
between HIV and AIDS. See for example Duesberg P. (1988) HIV is not the cause of AIDS.
Science 241: 514, 417. idem (1994) Infectious AIDS - stretching the germ theory beyond its
limits. International Archives of Allergy and Immunology 103: 118-127. See also Berridge V.
(1996) 'Orthodoxy and fringe': the anti-AIDS alliance, op. cit. note 90 above, 231-251.
202 See Darby S C, Ewart D W, Giangrande P L F, Dolin P J, Spooner J D, Rizza C R. (1995)
Mortality before and after HIV infection in the complete UK population of haemophiliacs.
Nature 377: 79-82.
Haemophilia: Recent history
Rizza: Don't let us assume that recombinant is perfectly safe. That is the next
step. You mustn't assume that. That will take 20 years of work, or ten years to
see the fallout. I hope it is perfectly safe, but you can't assume that.
Dr David Tyrrell: 203 I would like to mention one other group who were
involved, a group with whom I sat, namely the Biological Products
Subcommittee of the Committee on Safety of Medicines and its
predecessors. I always felt we were sitting in a rather hot seat in respect of the
successive applications which various manufacturers made for products derived
from blood. I think it is important to realize that from the very beginning
people knew that they were dealing with a gamble. Blood transfusion began as
we have heard in the 1930s and 1940s and that revealed the presence of hepatitis
viruses in blood. We knew also that although you could do some biochemistry,
there was no way of ensuring that they wouldn't be there in the product.
Therefore there is an aphorism used by people in this area, saying that the one
way of making a non-infectious product is to start with something that is non-
infectious. So, if you want to make a product that you are sure is non-infectious
the only place you know that you can find your product is in blood, that means
you don't make the product! As we were aware of this, it was part of the
documentation that every ampoule should have a warning that there was a risk of
infection. It was up to us to evaluate how the product had been made (which
would include its source, its processing and so on), and the physician who used
it to decide whether there was more benefit to the patient to have this product
or not to have it and receive some other form of management. The succession of
catastrophes as you described them parallel the series of advances in virology.
Once, as you said, we were worried about hepatitis B, but after some very hard
and very good work a way of testing for hepatitis B was discovered, 205 so it was
removed from the initial starting material. The same thing happened over
hepatitis A, then it happened over hepatitis non-A, non-B, now called hepatitis
C. I am recalling this because people have said that the manufacturers didn't
care. I have heard this said in emotional broadcasts, 'They didn't bother about
the fact that they might kill my child or whoever'. I think it is important to
203 Dr David Tyrrell CBE FRCP FRCPath FRS (b. 1925) was a member of the scientific staff
of the MRC Common Cold Unit at Salisbury from 1957 and its Director from 1982 until his
retirement in 1990. He was Chairman of the Spongiform Encephalopathy Advisory Committee
(SEAC), from February 1989 until 1995.
204 The Committee on Safety of Medicines (CSM) was created by the Medicines Act 1968 with
similar functions to the preceding Committee on Safety of Drugs, which operated from
January 1964 to September 1971, when the new Committee started. Along with the Committee
on Veterinary Products, it advises the Licensing Authority. See Tansey E M, Reynolds L A (eds)
(1997) The Committee on Safety of Drugs. In Wellcome Witnesses to Twentieth Century
Medicine, vol. 1. London: The Wellcome Trust, 103-135.
205 op. cit. note 181 above.
Haemophilia: Recent history
sometimes try and see it as a necessary corollary of the way science actually
works. As somebody said we actually do not go forward like a Horizon
programme suggests, with a hypothesis that is followed by a neat series of
experiments all of which build up to a tidy conclusion. We stumble forward,
and this is part of the stumbling; in the stumbling process we can do good on
the way and it's a matter of the art of medicine (which hasn't gone away I am
sure) to try and do the good and minimize the harm. But the aphorism which I
mentioned before still applies and supports what you have just said about
recombinant products. We know we can make recombinants in a bottle or a tube
which doesn't contain an infectious virus and if you want a non-infectious
product in the end, that must be a better place to start than one which is bound
to contain at some stage some infectivity.
Dr Angela Dike: 206 I worked at the Oxford Blood Transfusion Centre for the
last 19 years and what I wanted to say complements the previous speaker. I
would like to fill in a gap between the discovery of viruses in blood, and the
leap to the demand for recombinant plasma products. During this interval the
National Blood Transfusion Service made rapid progress towards improving
the safety of blood transfusion, by introducing a succession of increasingly
sensitive laboratory tests for the presence of hepatitis viruses and HIV in
individual blood donations, and by progressing towards very searching
questioning of would-be blood donors so as to exclude any with obvious
infection risks, so that blood transfusion now is considerably safer than it was in
the 1970s. 207
JoneS: I think that the last two speakers are obviously absolutely right and
perhaps it's what Christine said before: that haemophilia and what has happened
to people with haemophilia as a result of a viral infection has been a spur to a
lot of science. It was probably individual donor testing that made blood safer
rather than any of the early anti-HIV tests and the treatment of the blood
products themselves. I take what you [Tyrrell] are saying about the Committee
on Safety of Medicines, 208 but still blood products in this country that are
206 Dr Angela Dike FRCPath (b. 1936) joined the Oxford Haemophilia Centre in 1966 as a
medical registrar, when Rosemary Biggs and Gwyn Macfarlane were still working there, and
where she met Ross (see note 177 above), her husband. She became an Associate Specialist at the
Oxford Blood Transfusion Centre from 1977 to 1996 and is now retired.
207 Dr Angela Dike wrote: 'The risk of transmitting hepatitis B, hepatitis C or HIV in an
individual blood donation is now of the order 1 in 500 000. If plasma products were now
made from small pools they would, of course, be much safer than the products
being made nowadays from pools of 5000 or more individual blood donations.' Letter to
Dr Daphne Christie, 4 July 1998.
208 op. cit. note 204 above.
Haemophilia: Recent history
imported are not labelled with their country of origin. When I buy fishfingers
from Sainsbury's, I know where they have come from, and I know where my
honey comes from, but I don't know where blood products come from. I also
know that as well as hepatitis B, manufacturers knowingly imported blood
products which were known to be HIV positive. I also know that within the
European Community, and I have documentary evidence, there has been re-
labelling of blood products, unknown to the Committee on Safety of
Medicines. These things go on whenever you've got a product which is being
sold for profit and they are bound to happen, we have to say that they happen,
and it's our duty to try to stop them happening. We are involved with this very
much in the World Federation of Hemophilia in the developing world with the
companies at this moment, because we rely on the companies for the treatment
of haemophilia. We have to work with them and the best way of working with
them is to be open and honest and work towards a safe product. So I take
everything you say from the Committee on Safety of Medicines, but the
background of it is again what I refer to as secrecy. It's the difficulty of being
at the sharp end and facing a family and somebody with haemophilia with the
knowledge that things have gone wrong in the past, and not being completely up
to date with the Committee on Safety of Medicines, perhaps for very
legitimate reasons, for commercial secrecy reasons at the same time.
Lee: We can't leave this room tonight without discussing the history of
recombinant and I am looking at Professor Tuddenham who, as many people
will know, was involved in the purification of factor VIII that made this
possible. Ted could you just give us a little bit of the insight. Why did you
start purifying factor VIII?
Tuddenham: I began my career in pathology in 1969 in Liverpool where I
was an SHO [senior house officer] on a pathology rotation. One of the duties
was to treat the haemophiliacs under David Weatherall's 209 care. This involved
going down to what was called the tropical ward then, which was part of that
wonderful Victorian building that's now all boarded up in central Liverpool,
and filling out bag, after bag, after bag of cryoprecipitate, drawing it up in
syringes and injecting it very slowly and I found this a terribly primitive,
209 Professor Sir David Weatherall Kt FRCP FRCPath FRS is Regius Professor of Medicine
at the University of Oxford, since 1992, Honorary Director of the MRC Molecular
Haematology Unit, since 1980 and a Wellcome Trust Governor since 1990. He was Nuffield
Professor of Clinical Medicine at the University of Oxford from 1974 to 1992 and Fellow of
Magdalen College, Oxford, from 1974 to 1992, Emeritus Professor since 1992. He has been
President of the British Society for Haematology since 1980 and the International Society of
Haematology, since 1992.
Haemophilia: Recent history
intriguing process. I started talking to haemophiliacs. We had one patient who
didn't respond at all and I went along to the lab and tried to sort it out with
Alan Smith, the technician, and we came to the conclusion that there had to be
an inhibitor, so it sort of sparked off my interest in haemophilia. Then I got a
job in Cardiff with Arthur Bloom 210 and that really was what got me launched
on the serious study of blood coagulation. That was 1971. At that time there
were a lot of confusing ideas around as to the nature of haemophilia and von
Willebrand's disease, recognized as a separate and distinct genetic entity, and
there were rival theories which were really quite hotly contested in the
literature. One idea was that there was just one molecule of factor VIII
which was also deficient in von Willebrand's disease, and a biochemist called
McKee in the States refused to be convinced that you could in any way separate
the von Willebrand property, the platelet adhesion-promoting property, from
the coagulation-promoting property. At one point if you said that they were in
any way separable you couldn't actually get the thing published in either the
Journal of Biological Chemistry or the Journal of Clinical Investigation which I
presumed was because he was a reviewer. A great advance, as has already been
mentioned, was made in 1971 by Zimmerman, Ratnoff (the other proposer of a
cascade hypothesis) and Powell who had raised an antibody that detected a line
in the plasma of severe haemophiliacs, but no line 212 in the plasma of a severe
von Willebrand's disease patient, which they called factor VHI-related
antigen. 213 There were various names floating around for this, including
antihaemophilic factor antigen, while the coagulation-promoting activity was
also called various things.
When I arrived in Cardiff, Arthur Bloom had just started putting together
all these differing and confusing biochemical, immunological and genetic
results. He called us into his office one morning in 1972 to give us the benefit of
his way of explaining all of this. He said there had to be a high molecular
weight protein that's deficient in the von Willebrand's disease and a low
210 Professor Arthur L Bloom (1930-1992) was one of the first to establish factor VIII and von
Willebrand's factor as separate molecular entities. He was awarded a Personal Chair in
Haematology in Cardiff in 1976 and was a past President of the British Society of
Haematology and of the British and International Societies of Haemostasis and Thrombosis.
He was Chairman of the United Kingdom Haemophilia Centre Directors Organization from
1979 to 1985.
211 For example McKee maintained that the two activities - antihaemophilic and platelet
adhesive - are properties of one molecule. McKee P A (1981) Observations on structure
function relationships of human antihemophilic/von Willebrand factor protein. Annals of the
New York Academy of Sciences 370: 210-226.
212 See note 12 above.
213 Zimmerman T S, Ratnoff O D, Powell A E. (1971) Immunologic differentiation of classic
hemophilia (factor VIII deficiency) and von Willebrand's disease. Journal of Clinical
Investigation 50: 244-254. Kernoff P B, Rizza C R. (1973) Factor- VHI-related antigen in
female haemophilia. Lancet ii: 734.
Haemophilia: Recent history
molecular weight protein deficient in haemophilia A that's coded on the X
chromosome. They are associated together in plasma and you can separate
them, as had been shown earlier by Owen and Wagner. 214 A high molecular
weight protein would be involved in platelet adhesion, but also in supporting
factor VIII in the circulation. This was to explain why, if you infused plasma
or factor VIII concentrate into a patient with von Willebrand's disease there
appeared in the circulation more factor VIII activity than you had infused in
the first place.
The other thing he did that got me absolutely hooked on biochemical
coagulation, was he paid for me to go to a meeting of the International Society
of Thrombosis and Haemostasis in Vienna in 1973. At that meeting Stephan
Magnusson announced the complete primary amino-acid sequence of bovine
prothrombin. 215 I thought, 'Right, I want to get the complete amino-acid
sequence of factor VIII'. It took another 12 years, but that is what originally
inspired me. I also had the privilege of having a waltz in Vienna with Katharine
Dormandy, who became significant later in my life. I also bumped into
Rosemary Biggs in the street when I'd got lost and asked her the way to the
conference centre and she gave me directions. As far as I can remember that was
the first and last time that I had any kind of interaction, social or scientific,
with the research group in Oxford.
In 1976 I had the opportunity to go to the States after I had completed
my training, got the various bits of paper, and Arthur Bloom got me a job with
Leon Hoyer who was the other most prominent researcher on factor VIII at that
time. He had started on separating factor VIII from von Willebrand's factor
and I spent two very happy years there. We had an antibody to the von
Willebrand's factor, which enabled us to grab the whole complex out of
plasma, and then we could elute factor VIII with, as it happened, 0.24 M
calcium chloride, which was free of von Willebrand's factor, and we were able
to start doing some biochemical studies on that. We published that data, 217 then
21 See for example Hurt J P, Wagner R H, Brinkhous K M. (1966) Human antihaemophilic
factor (AHF) purification: a comparison of two procedures. Thrombosis et Diathesis
Haemorrhagica 15: 327-337. Wagner R H. (1968) Recommendations of the subcommittee on
human factor VIII (AHF) and factor IX (PTC) preparations, ibid. 35: 235-237.
Magnusson S, Sottrup-Jensen L, Claeys H, Zajel M, Patersen T E. (1975) Complete primary
structure of prothrombin. Partial primary structures of plasminogen and hirudin. Thrombosis
et Diathesis Haemorrhagica 34: 562-563.
216 See for example Hoyer L W, DeLos Santos F R P and Hoyer J R. (1973) Antihemophilic
factor antigen - localization in endothelial cells by immunofluorescent microscopy. Journal
of Clinical Investigation 52: 2737-2744. Hoyer L W. (1975) Factor VIII subunits. Annals of the
New York Academy of Sciences 240: 84-94.
217 Tuddenham E G, Trabold N C, Collins J A, Hoyer L W (1979) The properties of factor
VIII coagulant activity proposed by immunoadsorbant chromatography. Journal of Laboratory
and Clinical Medicine 93: 40-53.
Haemophilia: Recent history
I came back to the Royal Free and set up a small lab to start trying to do this
on a larger scale. We did have support from the MRC towards developing
monoclonal antibodies and these were absolutely key. Over the next three years,
especially with the help of Alison Goodall, we got monoclonal antibodies to
factor IX which were the first monoclonals to a clotting factor, to factor VII
and to factor VIII, and I remember talking to the head of the transfusion
service at Elstree during that period, suggesting to him that the future of high
purity for blood coagulation factors would be monoclonal purification. For
various reasons, which we haven't got time to go into, they didn't get taken up
by the transfusion service here. It is now, of course, used by all commercial
laboratory concerns for high-purity fractionation.
In our efforts to purify factor VIII we worked with Speywood; David
Heath ran Speywood in Wrexham and he'd been developing a method of
making pig factor VIII which would be free of the platelet-clumping activity
which Charles Rizza referred to earlier, and I was very interested in his story of
patients seeing stars. When you purify pig factor VIII you also get pig von
Willebrand's factor and that directly aggregates human platelets, so to get a
good product, you need to get rid of that. Something that Alan Johnson, 219 who
was also mentioned earlier, had developed was a process for purifying factor
VIII, human factor VIII he was working with, which would get rid of the von
Willebrand's factor and give you mainly factor VIII. The problem with
dissolving the early concentrates was that they were actually a heavy cake of
fibrinogen and fibronectin with an extremely light contamination of factor
VIII, more or less just sort of a little bit of a dirty scum on the main cake of
stuff. So getting rid of all that was very important. We formed a collaboration
with Speywood to have a major go at purifying factor VIII, which we achieved
by 1982, and went to a congress in San Diego where we announced that. We
got talking to Genentech Inc. and as they say the rest is history; we purified
about 20 milligrams of factor VIII from about 2000 litres of human blood,
and that was sequenced and enabled the cloning and expression of recombinant
factor VIII. Over this period I have always felt that what we should be aiming
218 Speywood Laboratories (Wrexham, UK) prepared a highly purified antigen using Maws
porcine factor VIII material. See note 53 above.
219 See note 35 above.
220 Tuddenham E G, Lane R S, Rotblat F, Johnson A J, Snape T J, Middleton S, Kernoff P B.
(1982) Response to infusions of polyelectrolyte fractionated human factor VIII concentrate in
human haemophilia A and von Willebrand's disease. British Journal of Haematology 52:
221 These conference proceedings were not published. Results were published later in 1985, see
Rotblat F, O'Brien D P, O'Brien F J, Goodall A H, Tuddenham E G D. (1985) Purification
of human factor VIILc and its characterisation by Western blotting using monoclonal
antibodies. Biochemistry 24: 4294-4300.
Haemophilia: Recent history
at is the highest level of biochemical purification, first to produce high-level
purity concentrates that are free not just of viruses but of the other unwanted
side-effects of infusing very impure concentrates. Secondly, to lead into the era
of molecular biology, because the purpose of sequencing factor VIII was to
enable its cloning by the classical biochemical route and to enable synthesis.
I heard Charles Rizza mention that it has yet to be proved that the
recombinant material is completely safe and, of course, I would agree with
that. Everything that we give to a patient has to be subjected to the most intense
scrutiny and I think I would say, and others might agree, that the trials of the
recombinant material have been more intensively scrutinized and more
extensively followed than the introduction of any other blood products have
been in the past. Of course, we have had the benefit of hindsight, learning from
the problems of introducing other concentrates that weren't sufficiently closely
followed at the time. Up to this point, I am not aware of any serious or indeed
any complication of using recombinant material for treating haemophiliacs,
other than the development of inhibitor antibodies, 222 another large issue we
don't have time to go into, but up to this point they appear to have a perfect
safety record. The only down side that I can see is that we are still using
plasma-derived albumin as the protein for the carrier for these concentrates, the
recombinant concentrates, but shortly that will surely be replaced with
Lee: It's interesting that the first patient in the UK who had recombinant, I
think, was in 1988. We at the Royal Free continued treating a second patient
until 1994 when it was licensed. Promptly when it became licensed that patient
had to be treated with plasma-derived concentrate, because it was too expensive
to continue giving him the recombinant. It's with that really in mind that I
thought we should end with a note of where we are at now. Peter Jones alluded
to the fact that the UK Haemophilia Centre directors have guidelines 223 which
recommend that patients should be treated with recombinant factor VIII which
is licensed now, and recombinant factor IX when it becomes licensed and we
are reasonable people and we realize that there isn't a bottomless pit, so we've
suggested that children should be the priority. In this country, I think there are
about 600 children with severe haemophilia A and half of them are being
222 Nilsson I M, Berntorp E, Zettervall O. (1988) Induction of immune tolerance in patients
with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG,
cyclophosphamide and factor VIII. New England Journal of Medicine 318: 947-950. Hoyer L W.
(1995) Factor VIII inhibitors. Current Opinion in Hematology 2: 365-371.
223 United Kingdom Haemophilia Centre Directors Organization Executive Committee.
(1997) Guidelines on therapeutic products to treat haemophilia and other hereditary
coagulation disorders. Haemophilia 3: 63-77.
Haemophilia: Recent history
treated with recombinant as of now, and the other half aren't for reasons of
economics. I thought it would be helpful to really tie up the issues of cost and I
want to refer again to Dr Biggs's interview. 224 She talked about the factor VIII,
this was in the 1970s, being on the pharmacy budget and she said, 'Yes it was,
we used more than half the area's money for medicine, just on haemophilic
patients'. At the Royal Free we spend £10 million a year on haemophilia and I
think the total hospital budget is £124 million pounds, so it's a tenth of the
Before I hand over to Clifford [Welch] to talk about this issue, I think we
have to remind Ted that some of his research, since we are in the business of
reminding who's helped in this business, was actually funded by The Katharine
Dormandy Trust. 225
In the summer, Clifford, who doesn't mind me sharing with you that he has
mild haemophilia, had a terrible bout of cholecystitis. He was pretty close to
going, and he had his gall bladder removed using continuous infusion of
recombinant factor VIII, so I think he understands where we have been and
where we have arrived at, and he certainly understands the problems of the
economics of delivering this care in 1998.
Welch: I'll be very, very brief because time is getting on, but to me the last
65, 70 years, have been quite extraordinary. I trained as a scientist and
therefore, although I have no special knowledge of medicine, I do have some
knowledge of research. To see what an extraordinary transformation has
occurred from the time when I remember going, as I mentioned earlier, to
Bart's with one of my brothers and my mother, to today. This boy was
practically at death's door, and I vividly recall the expression on the faces of
the house surgeon and physicians who were trying to deal with a situation totally
outside their experience. They didn't know what to do. Today we have these
extraordinary developments. Despite the scourge of HIV and hepatitis C, the
fact is that we can now expect to live normal lives as haemophiliacs, to grow up,
to have children, and to see our children
grow up as normal children too and 30, 40, 50 years ago that was certainly not
As a result of all that Katharine Dormandy achieved, she, like Gwyn
Macfarlane, had a profound influence upon my life and enthused me
enormously, by virtue of the unwavering dedication she gave to her patients. I
op. cit. note .
22 ' Dr Katharine Dormandy, Director of the Centre for Haemophilia and Haemostasis, set up
the Trust Fund in 1971; see biographical note 111 above.
Haemophilia: Recent history
felt that one had got to try to put something back. And one of the things that we
have been trying to do with Katharine Dormandy's Trust down the years is to
make sure that her objective of searching for a cure for haemophilia and
relieving the distress caused by this inherited disease should be prosecuted with
all the vigour that we can.
It was in 1996 at the Royal Free that we first realized that the other side of
the coin of this great success in treating haemophilia was the fact that it was
costing so much money. Peter Jones mentioned before tea that haemophilia is 'a
bloody nuisance to everybody'. And indeed it is, and it has become an
increasing nuisance in the sense that whilst recombinant factor VIII should
obviously be the treatment of choice, particularly for children, so that they
grow up without running the risk, or too great a risk, of other side-effects. So is
this refined treatment that much more expensive? The fact remains that we were
finding at the Royal Free in 1996 that we had patients side by side, one boy
being treated with recombinant material and the boy next door not, simply
because some of the purchasing authorities buying the services in the hospital
were prepared to pay the extra cost and some were not. And when one looks at
the enormous cost and the ever-increasing demand for money within the
National Health Service, one realizes what a dreadful dilemma this is.
What we did at the Royal Free in 1996 was to set up a task force, initiated
by Martin Else, the Chief Executive of the hospital, which for the first time
brought together all of the different disciplines to address the problem. In the
past the Haemophilia Centre, important though it is, is when seen against the
totality of the work going on in the hospital, a very small unit in a great
enterprise. It was the first time that we brought together the legal people, the
purchasing officers, all the different experts who were responsible in their
individual way for moving things forward and we said to them, 'How are we
going to persuade the funding bodies to give us the money, what techniques can
we use, ranging from blackmail to appeal, to bursting into tears if you like, and
secondly what proposals could we put forward to deal with this problem which
was clearly going to get worse year by year and which was going to get ever
more expensive'. The first part of the problem was successively resolved in the
sense that in 1997 all of the young children at the Royal Free were on
recombinant treatment. What's going to happen in 1998 and 1999, heaven
knows! Possibly we shall still be having these arguments with the individual
purchasing trusts as long as the concept that 'money follows patients' exists. But
the more important outcome was that we were able to develop a detailed
report to propose a national specialist commissioning advisory group to take
this problem over as a national problem rather than it being regarded as a local
problem for individual health authorities. And that report derived precisely
Haemophilia: Recent history
from the fact that Katharine Dormandy's Trust gave us the opportunity, and the
authority to get on with the job. I hope that the effect will be to lift this
particular cost problem out of the domain of the individual purchasing trusts on
to a more national basis. Whether that is a hope that has foundation remains to
be seen, but I do very, very much pay tribute this afternoon to all of the people
who have given so much to haemophiliacs, from Rosemary Biggs, Ethel
Bidwell, Gwyn Macfarlane, Charles Rizza, Ted Tuddenham, Katharine
Dormandy, Peter Kernoff, to all the other specialists in this area.
Lee: Has anybody got some final comments that they are burning to
contribute? I would like then to thank everybody. I speak for myself and say I
don't think I have spent such an interesting afternoon for many a long day. I
think it has been absolutely fascinating, and I think we should all be very
grateful to the people who have travelled for very long distances.
Tansey: On behalf of the Wellcome Trust, I would like to thank you all for
participating in this afternoon's seminar. Speaking as a historian who came here
knowing very little about haemophilia, it has been a great privilege listening to
the accounts and I am convinced that the edited transcript of this meeting will
be a valuable resource for future historians who will want to know about
haemophilia at the end of the twentieth century. May I add my particular
thanks to our Chairman, Christine Lee. We actually set this in motion only four
months ago and had to put this meeting into our programme at very short
notice. The driving force behind this meeting has come from Christine and I
hope you will join me in thanking her.
Haemophilia: Recent history
Classical Theory of Blood Clotting 1
A three-stage process involving conversion of fibrinogen into fibrin following thrombin formation.
1 . Platelet breakdown ► Thromboplastin
Tissue damage ► Thromboplastin
2. Prothrombin + Thromboplastin + Ca 2+ ► Thrombin
3. Fibrinogen + Thrombin ► Fibrin
A Present Day Theory 2
Kallikrein + foreign surface (collagen, platelets)
VII + III (Tissue thromboplastin)
-*• Activated XII
> Activated XI
IX ►Activated IX + VIII + platelet phospholipid + Ca 2t
-> Activated X 4-
Activated X + V + platelet phospholipid + Ca 2+
-> Activated II (prothrombin)
-► Fibrin — — ► Fibrin clot
Blood Coagulation Factors
Labile factor, proaccelcrin
Stable factor, proconvertin
Antihaemophilic globulin, antihaemophilic factor A
Christmas factor, antihaemophilic factor B
Plasma thromboplastin antecedent
1 Adapted from Morawitz P. (1905) The chemistry of blood coagulation.
Ergebnisse der Pbysiologie 4: 307—422.
2 See for example O'Neil R. (1988) The blood. In Emslie-Smith D, Paterson C R, ScratcherdT,
Read N W. (eds) Textbook of Physiology. Edinburgh: Churchill Livingstone, 35-36.
Haemophilia: Recent history
Acquired immune deficiency syndrome
(AIDS) - A condition linked to the
retrovirus, human immunodeficiency
Anaphylactic reaction - An acute allergic
response following injection of, or
exposure to, a foreign protein or other
substance, caused by the release of
histamine or another vasoreactive
Antihaemophilic globulin (AHG) —
See factor VIII.
Arthropathy — The abnormality seen in
joints of haemophiliacs after repeated
episodes of spontaneous bleeding (e.g.
secondary gross degeneration of the
articular cartilage and bone).
Bethesda unit - A unit used in the
measurement of inhibitors arising in
haemophiliacs (see note 83).
Bleeding time — The time during which a
small puncture or incised wound in the
skin (made under controlled
conditions) continues to bleed,
normally less than ten minutes.
Calcium-clotting time — The time for
coagulation to occur when calcium
chloride is added slowly to a mixture
of saline and citrated plasma. With
normal plasma the clotting time ranges
from 90 to 250 seconds.
Christmas disease - See haemophilia B.
Christmas factor - See factor IX.
Clotting time - A test of the clotting
mechanism and the amount of
Creutzfeldt-Jakob disease (CJD) -
A disease in which spongiform
encephalopathy virus is implicated.
Cross-correction — The haemophilic
patient's plasma corrects, and is
corrected by, the plasma of a known
haemophiliac (see note 16).
Cryoprecipitate - The plasma fraction
that is obtained by freezing (— 20°C)
and then thawing (4°C) normal human
plasma. When frozen plasma is thawed
slowly, the last proteins to dissolve
include fibrinogen and factor VIII,
and these make up the cryoprecipitate
(see note 24).
DDAVP — l-deamino-8-D-arginine
vasopresssin (desmopressin). A synthetic
analogue of the antidiuretic hormone
L-arginine vasopressin, raises factor
VIII levels when infused into healthy
Desmopressin — See DDAVP.
Extrinsic (coagulation cascade) pathway -
The pathway where tissue factors are
required from outside the plasma in
the process of coagulation (see
Factor VII - A plasma coagulation factor
intermediate in the clotting cascade
(see Appendix). It normally circulates
in an inactive form.
Factor Vila - Activated factor VII.
Contact with tissue extracts (released by
tissue damage) converts factor VII to an
active form, factor Vila. (The pathway
is different from that involving factor
VIII, so factor Vila can lead to clot
formation in the absence of factor
Factor VIII (antihaemophilic globulin
(AHG)) - A plasma coagulation factor
whose inherited deficiency is
responsible for classic haemophilia
(lack of factor VIII:c) or von
Factor VIIIx - The coagulant moiety of
the factor VIII complex, primarily
deficient in classic haemophilia.
Factor IX (Christmas factor) - A plasma
coagulation factor that may be
deficient on an inherited basis
Fibrinogen — The precursor of fibrin in
Haemarthroses - Joint bleeds.
Haematurea - Excretion of urine
Haemophilia - A hereditary bleeding
disorder which affects the clotting of
blood (see haemophilias A and B).
Haemophilia A* - Factor VIII deficiency.
Haemophilia B* - Factor IX deficiency
Haemostasis - The arrest of haemorrhage.
Hepatitis - Inflammation of the liver.
Human immunodeficiency virus (HIV-1)
— The retrovirus linked to AIDS,
formerly AIDS-related virus.
Inhibitor patients - Individuals who raise
antibodies to factor VIII.
Intrinsic (coagulation cascade) pathway -
Intrinsic to plasma since all factors
can be generated from plasma
Kallikrein - The enzyme that releases
bradykinin from the plasma protein
Platelet - Platelets are present in large
numbers in blood and play an
important role in blood clotting.
Properties of adhesion and aggregation
allow haemostasis when vascular
endothelium is damaged, and also
(see Appendix) .
Port-a-Cath - A device used when
treatment into a vein is needed
regularly. One end of the catheter lies
in the right atrium of the heart. The
other end, which provides access for
injection of treatment, is either
implanted under the skin of the chest
wall or is taped to it.
Prothrombin - A plasma protein yielding
thrombin following activation by
Radiosynovectomy - A non-operative
technique of injecting a
radioactive isotope into the
joint (see synoviorthrosis).
Synovectomy — The excision of the
synovial membrane that lines a joint
or tendon sheath, used to treat chronic
haemophilic arthropathy. It reduces
but does not abolish further bleeds as
it is rarely complete.
Synoviorthrosis - The technique of using
isotopes (e.g. radiocolloids) to produce
fibrosis of the synovial membrane and
hence reduce bleeding and subsequent
Thrombasthenia - An autosomally
inherited haemorrhagic disease
with unique abnormalities of
Thrombin — A proteolytic enzyme which
induces clotting by the conversion of
fibrinogen to fibrin.
Thrombocytopenia - A deficiency
of platelets often associated
Thromboplastin generation test - A test
for the efficiency with which
thromboplastic activity appears in a
mixture of coagulating blood
von Willebrand's disease* - An inherited
bleeding disease resulting from a
deficiency or abnormality of the
von Willebrand factor part of the
plasma coagulation factor VIII
complex. Clinical features include
prolonged bleeding time and reduced
♦Haemophilias A and B are inherited in a sex- Linked manner, while von WJJehrand^ disease
is inherited as an autosomal dominant condirioji.
Index : Subject
acid-citrate-dextrose (ACD), 29
accelerated degradation tests, 20, 21
acquired immunodeficiency syndrome,
AHG, see antihaemophilic globulin
AIDS, 64, 67, 80, see also human
as 'bystander effect', 68
first cases in haemophiliacs, 26
litigation, 63, 65-66
albumin, 30, 75
allergic reactions, 33, 80
anaphylactic reactions, 14, 16, 80
animal factor VIII concentrates, 13-15, 33,
see also bovine antihaemophilic
antenatal diagnosis, 26, 27
antidiuretic hormone, 1 1
antifibrinolytic drugs, 7
antihaemophilic globulin (AHG), 43, 44,
80, see also factor VIII
animal, preparation, 48-51
bovine, see bovine
human, see factor VIII
porcine, 7, 14, 74
arthritis, haemophilic, 36
arthropathy, haemophilic, 80, 81
Australian antigen, 62
Barcelona, Public Health
Baxter (UK), 25
Bethesda unit, 25, 80
acute episodes, 6, 33, 35, 40
time, 6, 80, 81
tissue destruction, 17
blood, see also plasma
coagulation, see coagulation, blood
donors, 24-25, 55-56, 70
products, safety, 69-71
Blood Products Laboratory, Elstree,
19, 29, 30, 38, 59, 60
blood factor purification, 73-74
plasma fractionation methods, 19
early, 6-7, 33, 40
equipment, 28-29, 32-33
services, origins, 23
Blood Transfusion Service, National, 23
availability of blood products,
24, 25, 33, 35-36, 38, 60
safety of blood transfusion, 27, 70
Booth Hall Children's Hospital,
Manchester, 22, 23
bovine antihaemophilic globulin
(factor VIII), 7, 12
clinical use, 14-16, 17
preparation, 13-14, 61
brain, thromboplastic activity, 43-44
Bristol Transfusion Centre, 30
British Haemophilia Society, 7
British Medical Journal, 45-47
British Working Standard, 21
calcium-clotting time, 80
carriers, haemophilia, 4
catheters, see venous; Port-a-Caths
cerebral haemorrhage, 24
Chapel Hill, North Carolina,
United States, 8
blood transfusions, 33, 35
home treatment, 37
hospitals, 27, 37
recombinant factor VIII therapy, 74, 77
Christmas disease (factor IX deficiency),
discovery, 6, 8, 9-10, 44-45, 46
early treatment, 12
factor IX concentrate therapy, 18-19
origin of name, 46, 47
Christmas factor, see factor IX
chromosomes, autosomal, 80
Churchill Hospital, Oxford, 12, 32, 61
citrate-phosphate-dextrose with adenine
CJD, see Creutzfeldt-Jakob disease
cloning, factor IX and VIII genes, 26, 74
blood, see coagulation, blood
time, 5, 10, 80
coagulation, blood, 43-44, 79
cascade hypothesis, 45
classical theory, 79
extrinsic pathway, 43, 79, 80
factors, 5, 79
intrinsic pathway, 43, 79, 81
Cohn's fibrinogen fraction, 12
colour blindness, 7
Commi tt ee on Safety of Medi ci nes, 69, 70-71
concentrates, see also factor IX, concentrate;
factor VIII, concentrate
availability, 25, 29-30, 33, 35, 36, 38
continuous infusions, 28-29
freeze-dried, 7, 20, 25, 34
heat treatment, 64
HIV contamination, 25, 30
home treatment, 34, 36
imported from USA, 25, 30, 36,
manufacture, 53, 54
storage at home, 34, 35
viral contamination, 26, 28, 62-71
coronary thrombosis, 42
coumarin plasma/serum, 43, 44
Creutzfeldt-Jakob disease (CJD), 28, 40,
new variant (nvCJD), 63-64, 66
Crookes Healthcare Ltd, 17
cross-correction (mixing) experiments,
6, 8, 9-10, 44-45, 80
availability, 24, 25, 36
discovery, 7, 35
HIV contamination, 25
home treatment, 33-34, 35, 36, 37, 39
cystic fibrosis, 37
cysts, haemophilic, 16-17, 32
vasopressin, desmopressin), 7, 10-11, 80
dental extraction, 7, 14, 42
Department of Health (and Social
(DHSS), 54, 64
availability of blood products and, 30,
Haemophilia Register, 60
HC-76/4, publication, 26
Health Services Guidelines (93/30), 28
MRC and, 59, 60
desmopressin (DDAVP), 7, 10-11, 80
developing countries, 57, 71
antenatal, 26, 27
of haemophilia, 8-9, 10, 26-27
drug users, 59
economic aspects, haemophilia therapy, 35,
Edgware Transfusion Centre, 21
egg white, Timperley's, 41, 52, 53
Elephant and Castle, Department of
Health and Social Security, 59, 60
Elstree, see Blood Products Laboratory,
epistaxis (nose bleed), 43
epsilon-aminocaproic acid, 7
availability, 13, 47, 61
made of Meccano, 40, 41, 47
transfusion/infusion, 28-29, 32-33
European countries, 36
exercise, factor VIII levels after, 1 1
extrinsic pathway, see coagulation, blood
factor V (labile factor), 42, 44, 45, 79
factor VII, 42-43, 44, 79, 80
activated (factor Vila), 26, 80
cryoprecipitate, 62, 71, 80
Index : Subject
factor VIII, 79, 80, see also
assays, 5, 20-22, 26, 45
concentrate, 7, 12-17, see also bovine
antihaemophilic globulin; porcine
availability, 25, 29-30, 33, 38, 60
continuous infusion, 28-29
early clinical use, 14-16, 17, 24
freeze-dried, 7, 20, 25
human, 15, 16
i ni tial preparati on, 12-1 4, 44, 48-51 , 61
manufacture, 15, 17, 53
cryoprecipitate, see cryoprecipitate
DDAVP therapy and, 1 1
deficiency (haemophilia A), 75, 81
discovery, 4-5, 12
effects of adrenaline, 10-11
effects of exercise, 1 1
function, 45, 79
gene cloning, 26—27, 74
immunological detection, 5
inhibitors (antibodies), see inhibitors,
long-term stability, 21
recombinant, 28, 67, 74
availability, 62, 75
economic aspects, 75-77
guidelines on use, 74
safety, 68, 70
sequencing, 73, 74
standards, 5, 20-21
in von Willebrand's disease, 6,81
von Willebrand's factor and, 72-73, 74
factor VHI-related antigen, 72
factor IX (Christmas factor), 79, 80
first clinical use, 18-19
preparation, 19, 61
deficiency, see Christmas disease
gene cloning, 26
recombinant, 67, 75
haemophilic, 4, 17
transmission of haemophilia, 4
fetal blood sampling, 26
fibrinogen, 44, 79, 80
factor VIII separation, 12, 61, 74
fraction, Cohn's, 12
Food and Drug Administration (FDA), 63
fractionation, plasma, see plasma,
freeze-dried concentrate, 7, 25, 34
freezers, 34, 35
gangrene, 13, 18, 19
Genentech Inc., 74
genetic counselling, 56
Glasgow Royal Infirmary, 43
Government, 57, 62
HIV infection and, 64-65
safety of blood products and,
30, 55-56, 67
Great Ormond Street Hospital,
London, 22, 39
gun shot wound, patient with, 14, 16
haematologists, 20, 24, 26
haematuria, 43, 81
A, 75, 81, see also factor VIII
B, see Christmas disease
care, 3-4, 22, 26, 38-39, 53
diagnosis, 8-9, 10, 26-27
distinction of two types,
mild, 5,7, 10-11,40
origin of name, 4
treatment, see treatment of haemophilia
von Willebrand's disease and, 5-6,
Haemophilia Centres, 6, 53, see also
Kingdom Haemophilia Centre
Directors Organization; Katharine
Dormandy Haemophilia Centre
annual returns, 53-54
comprehensive care, 38, 39
concentrate supplies, 38
Haemophilia Society and, 56
three-tier system, 26
two-tier system, 28
Haemophilia Society, 23, 26, 47, 54-56, 58
beginnings, 7, 22, 41, 54-55
HIV infection and, 56, 65, 66
lobbying function, 55-56, 65, 66
Manchester meeting, 27
premises, 54, 55
haemorrhoid surgery, 19
haemostasis, 41, 81
Hammersmith Hospital, London,
Health Services Guidelines (93/30), see
Department of Health
heart failure, 24, 35
heat treatment, 64
hepatitis, 21, 40, 56, 62-63, 81
A, 28, 69, 81
B, 62-63, 69, 70, 81
C,28,63, 66, 69,70, 81
non-A, non-B, 63, 69
prevention of transmission, 64
hip fracture, 17
HIV, see human immunodeficiency virus
home treatment, 33-35, 36-38, 39, 63
availability of supplies for, 35, 36
concentrate storage, 34, 35
resistance to, 36
hospitals, children's, 27, 37
human factor VIII concentrate, 15, 16
human immunodeficiency virus (HIV),
63-68, 81, see also AIDS
contaminated blood products, 25, 30,
infection, 40, 67-68
Haemophilia Society and, 56, 65, 66
litigation, 63, 65-66
recompense for, 65
in Scotland, 59, 65
surgery in, 30-31, 32
-positive children, 27-28
television advertisements, 27
testing, 27, 70
hypothalamic-pituitary axis, 1 1
intrinsic pathway, see coagulation, blood
jaundice, 67, see also hepatitis
John Bell and Croyden, London, 40
joint bleeds (haemarthroses), 4, 81
kallikrein, 8 1
Katharine Dormandy Haemophilia
Centre, 34, 58
Katharine Dormandy Trust, 76, 77
labile factor, see factor V
Lawn Road Hospital, Hampstead, 34, 58
life expectancy, 31, 67
Lister Institute, Elstree, 19, see also Blood
Products Laboratory, Elstree
litigation, for HIV infection, 63, 65-66
Lord Mayor Treloar Hospital and
College, Alton, Hampshire 67
Macfarlane Trust, 3, 28, 65
Manchester, 22, 23, 24-25, 27, 60
Manchester Royal Infirmary (MRI), 23,
24, 25, 37
Maws & Son Ltd, 15, 17
Meccano, see equipment
Medical Research Council (MRC), 52, 53,
Blood Coagulation Research Unit,
Oxford, 12, 58, 61
Blood Products Laboratory, Elstree, 29,
Blood Transfusion Research
Central Workshops, 61
Haemophilia Committee, 58
Haemophilia Register, 59-60, 62
Park Crescent headquarters, 59, 60
Ministry of Health, 52, 53, see also DHSS
monoclonal antibodies, 73-74
MRC, see Medical Research Council
infusions, continuous, 28-29
inhibitors, patients with, 25, 71, 75, 81
factor Vila therapy, 26, 28
orthopaedic surgery, 32
International Haemophilia Society, 7
International Society of Thrombosis and
Haemostasis Meeting, 73
National Blood Authority, 60
National Blood Transfusion Service, see
Blood Transfusion Service, National
National Health Service, 52, 77
National Institute for Medical Research,
Biologi cal Standards Di vi si on, 5, 20-21 , 61
needles, 28-29, 33
Index : Subject
New York Medical Center, 21
Newcastle, 35, 39
Norwich, patient from, 14, 16
nose bleed (epistaxis), 43
Nuffield Orthopaedic Hospital, Oxford,
nurse, haemophilia, 37-38
nvCJD, see new variant CJD
orthopaedic surgery, elective, 31-32
Oxford, 3, 9-10, 39, 53
blood coagulation studies, 41-42, 43,
44-45, 58, 61
Blood Transfusion Centre, 13, 33, 70
factor VIII concentrate, 13-15
Haemophilic Unit, 30, 31-32
referral of patients to, 17, 18-19
HIV-positive children, 27-28
home treatment and, 36, 37, 39
views of one, 38-40
parvovirus, 26, 63
patients, haemophilic, 22, see also children;
life expectancy, 31, 67
plasma donation by, 8
recollections of, 40-41
peptic ulceration, 15, 17
cross-correction (mixing) experiments,
6, 8, 9-10, 44-45, 80
donation by haemophiliacs, 8
fractionation, 4-5, 12, 38
facilities, 30, 54, 59, 61, 62
methods, 19, 44
fresh-frozen, 24, 33, 35
plastics, 13, 15
platelets, 43, 44, 81, see also
clumping, 16, 72, 74
porcine antihaemophilic globulin (AHG,
factor VIII), 7, 14, 74
Port-a-Caths, 28-29, 81
pregnancy, termination, 26
prothrombin, 43, 79, 81
time, 4, 42, 43
Quick's one-stage prothrombin time test,
Radcliffe Infirmary, Oxford, 3, 9, 61
radiosynovectomy, 29, 31,81
recombinant products, see also factor VIII,
safety, 68, 70, 74-75
recompense, campaign for, 65
Red Cross, 23, 25
Register, Haemophilia, 59-60, 62
Registry, Haemophilia, 47, 53-54
rehabilitation, after orthopaedic surgery,
Royal Free Hospital, London, 17, 22,
36-37, 39, 73, see also Lawn Road
Hospital, Hampstead; Katharine
Dormandy Haemophilia Centre
recombinant factor therapy, 75, 77
Royal London Hospital, 17, 37-38
Russell's viper venom (Stypven), 6, 39, 40
St Bartholomew's Hospital (Bart's),
London, 40, 41,76
St Mary's Hospital, London, 29
St Thomas' Hospital, London, 4, 22
Scotland, 59, 60, 62, 65
SEAC, see Spongiform Encephalopathy
slaughterhouse, 13, 47
Spanish Civil War, 23
Speywood Laboratories, 74
spongiform encephalopathy, 63, see also
Spongiform Encephalopathy Advisory
Group (SEAC), 66, 69
standards, reference, 20-22, 25, 61
factor VIII, 5, 20-21
stars, seeing, 16, 74
Stypven, see Russell's viper venom
elective orthopaedic, 31-32
HIV-infected patients, 30-3 1 , 32
manufacture of factor VIII for, 15-16,
synovectomy, 29, 31,81
synoviorthrosis, 31, 81
synovitis, chronic, 31
termination of pregnancy, 26
thrombasthenia, 44, 81
thrombin, 4, 43, 44, 79, 81
thrombocytopenia, 11, 16, 81
thromboplastin, 44, 79
generation test, 6, 8-9, 43-44, 45,
time, partial, 8
thrombosis, 41, 42
Timperley's egg white, 41, 52, 53
tongue, bleeding, 46
tooth extraction, 7, 14, 42
transport, for disabled, 55
travel, by patients, 39-40, 57
treatment of haemophilia, see also surgery
early, 6-7, 12, 32-33, 39, 40-41,
economic aspects, 35, 75-77
factor IX concentrate, 18-19
factor VIII concentrate, 14-16, 17, 24
historical sequence, 28-29
home, see home treatment
mild disease, 10-11
recommended, 67, 75
resistance to, 35-36, 76
side-effects, 4, 62-71, 74
Tuta (Australia), 25
United Kingdom Haemophilia Centre
Directors Organization (UKHCDO),
beginnings, 28, 47, 52-53
guidelines on treatment, 75
HIV infection and, 64, 65-66
on safety of blood products, 67
United States of America, 73
concentrates from, 25, 30, 36, 55-56, 63
diagnostic tests, 8
vasopressin, 1 1
venous catheters, in-dwelling, 28-29
Victoria, Queen of England, and
viruses, ^rf/iofuirnanimmunodefi ci encyvirus
contami nati on of concentrates,26, 28, 62-71
volunteerism, 55, 56, 57
von Willebrand's disease, 5-6, 23, 81
haemophilia and, 5-6, 72-73
von Willebrand's factor, 72-73, 74, 81
Wellcome Foundation, 13
Wellcome Trust, 78
WHO, see World Health Organization
Wilkinson Committee, 58
World Federation of Hemophilia, 40, 47,
beginnings, 7, 57
safety of blood products, 66, 71
World Health Organization (WHO)
factor VIII availability, 30
international standards, 20, 21
Addis, T, 4
Alexander, B, 6
Allain, Jean-Pierre, 66
Evans, David, 22-29, 30, 37, 47, 63
Fildes, Paul (later Sir) 4
Bangham, Derek, 20-21, 61
Bergsagel, Danny, 14
Bidwell, Ethel, 7, 11, 12, 13-14, 15, 16,
18, 19, 20, 41-42, 47, 48-51, 61, 77
Biggs, Rosemary, 3, 6, 7, 8, 9, 10, 14, 16,
18, 19, 20, 21, 36, 41-42, 43, 44, 46,
47, 54, 58, 59, 67, 70, 73, 75, 77
Blomback, M, 7
Bloom, Arthur, 71-72, 73
Blumberg, Baruch Samuel, 62
Booth, Sir Christopher, 45-46
Brinkhous, K N, 8
Britten, Peggy, 57, 58
Brozovi_, Milica, 21
Bull, Sir Graham, 46
Bulloch, W, 4
Cash, John, 7, 11,62
Christie, Daphne, 6, 19, 20, 21, 29, 31,
32, 36, 43, 57, 59, 61, 65, 66, 70
Christmas, Stephen, 9, 10, 44, 46-47
Cohn, EJ, 12
Colvin, Brian, 17, 37-38
Dacie, John, 10, 44, 46
Dalrymple-Champneys, Sir Weldon,
Denson, Ken, 20
Dike, Angela, 70
Dike, Ross, 12, 14, 19, 47,
Dodsworth, Helen, 29-30, 59, 60
Doll, Sir Richard, 68
Dormandy, Katharine, 34-35, 37, 38,
39, 57, 58, 73, 76, 77
Douglas, Stuart, 6, 9-11, 41-45, 62
Duesberg, Peter, 68
Duran-Jorda, Frederico (Frederick),
Duthie, Robert, 18, 30-32
Else, Martin, 77
Goldstein, R, 6
Goodall, Alison, 73
Graham, J B, 5, 8
Grant, Jean, 33
Haldane, J B S, 7
Hardisty, Roger, 22, 39
Heath, David, 74
Hill, Graham, 55
Hopff, F, 4
Howarth, Sheila, 58, 60, 62
Hoyer, Leon, 73
Ingram, Ilsley, 4-8, 9, 10, 11, 12, 15, 16,
17, 22-23, 39, 47, 58
Jenkins, George, 37
Johnson, Alan, 9,21,74
Jones, Peter, 15, 17, 22, 27, 35-36,
37, 39, 57, 62-67, 70-71, 75, 76
Kekwick, Ralph, 7, 19, 20, 24
Kernoff, Peter, 34, 35, 77
Lane, S, 6
Larrieu, M J, 6
Lee, Christine, 3-4, 8, 9, 11, 12, 13,
14-15, 16, 18,20,22,31,32,33,
34, 38, 39, 41, 46-47, 53, 54, 56,
57, 58, 60, 62, 65, 66, 67, 68, 71,
Lewis, J H, 5
Macfarlane, Gwyn, 3, 5, 6, 7, 9, 10, 12,
13, 14, 15, 18, 20, 38, 40, 41-42, 45,
Mackay, M E, 19
McKee, P A, 72
Magnusson, Stephan, 73
Major, Rt Hon John, 65
Mannucci, P M, 7, 10, 11
Matthews, James, 7, 16, 32-33, 34
Merskey, Clarence, 5, 9-10, 44, 45
Miller, Riva, 36-37
Minor, G R, 5-6
Mollison, Patrick (Pat), 30, 58, 59
O'Brien, John, 10
Owen, David (later Lord), 55-56
Owren, P A, 42
Pavlovsky, A, 6, 10
Pitney, W R (Bob), 10, 44, 46
Pool, Judith (Judy), 7, 24, 35
Poole, John, 9, 10,45
Powell, A E, 72
Quick, A J, 4, 42
Ratnoff, O D, 5, 72
Reynolds, Lois, 69
Rizza, Charles (Charlie), 3, 7, 9, 10, 11,
12, 16, 17, 18-19, 20, 31-32, 34, 37,
38, 43, 52-54, 59, 60, 67-68, 7A, 77
Schnabel, Frank, 57
Shannon, A E, 7, 35
Skegg, Joyce, 21
Smallpeice, Victoria, 1 8
Smith, Alan, 71
Smith, Frank, 41, 52
Soulier, J P, 6, 7
Spooner, Rosemary, 37, 53-54
Stockford, Victoria, 55
Stratton, Frederick (Fred), 24, 25
Tanner, Alan, 38-39, 40, 54-56, 57, 66
Tansey, E M (Tilli), 3, 4, 10, 69, 78
Taylor, F H L, 5
Teitle, Jerry, 46
Thatcher, Margaret (later Dame), 65
Timperley, WA, 41
Tovey, Geoffrey, 30
Treves, F, 4, 17
Trueta, Joseph, 18, 23
Tuddenham, Edward (Ted), 34-35, 37,
67, 71-75, 77
Tyrrell, David, 66, 69-70
Vallet, Leon, 19
Wagner, R H, 8, 72
Walsh, P N, 7
Walton, Peter, 20
Watson, Irene, 55
Watson-Williams, Dr, 24
Waiters, David, 56, 65
Weatherall, Sir David, 71
Welch, Clifford, 36, 40-41,
52, 75, 76-77
Whitby, Sir Lionel, 22
Wilkinson, John, 23, 52, 58
Willebrand, E A von, 5-6
Witts, Leslie, 43
Wolf, Peter, 7, 24
Wright, Irving, 5
Zimmerman, T S, 5, 72